GCSH

Summary

GCSH (glycine cleavage system protein H, HGNC:4208) is a protein-coding gene on chromosome 16q23.2, encoding Glycine cleavage system H protein, mitochondrial (P23434). The glycine cleavage system catalyzes the degradation of glycine. It is a selective cancer dependency (DepMap: 39.5% of cell lines).

Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding,have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.

Source: NCBI Gene 2653 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple mitochondrial dysfunctions syndrome 7 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 161 total — 7 pathogenic, 6 likely-pathogenic
• GTEx eGene: eQTL in 36 tissues, sQTL in 16 (q < 0.05)
• Phenotypes (HPO): 55
• Cancer dependency (DepMap): dependent in 39.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.33 (intermediate), LOEUF 1.54 (unconstrained)
• MANE Select transcript: NM_004483

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4208
Approved symbol	GCSH
Name	glycine cleavage system protein H
Location	16q23.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000140905
Ensembl biotype	protein_coding
OMIM	238330
Entrez	2653

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 21 protein_coding, 8 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000315467

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 2, TSL 5: 4

ENST00000315467, ENST00000561801, ENST00000564386, ENST00000564477, ENST00000566566, ENST00000569885, ENST00000639137, ENST00000639169, ENST00000639689, ENST00000640150, ENST00000879489, ENST00000879490, ENST00000879491, ENST00000879492, ENST00000879493, ENST00000984508, ENST00000984509, ENST00000984510, ENST00000984511, ENST00000984512, ENST00000984513, ENST00000984514, ENST00000984515, ENST00001091819, ENST00001091820, ENST00001091821, ENST00001091822, ENST00001109844, ENST00001130106, ENST00001139616

RefSeq mRNA: 1 — MANE Select: NM_004483 NM_004483

CCDS: CCDS10933

Canonical transcript exons

ENST00000315467 — 5 exons

Exon	Start	End
ENSE00000945534	81096131	81096395
ENSE00001319527	81081945	81082963
ENSE00003483947	81090601	81090680
ENSE00003491124	81087601	81087664
ENSE00003629376	81084463	81084594

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1458 / max 108.5483, expressed in 1746 samples.

Highest expression (Bgee): C1 segment of cervical spinal cord, substantia nigra, amygdala, temporal lobe, putamen.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GCSH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 16 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 52 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.7e-55	-1.89	16:81084918:T:C
Cells EBV-transformed lymphocytes	eqtl	2.7e-34	-0.57	16:81094409:G:T
Skin Not Sun Exposed Suprapubic	eqtl	9.1e-25	-0.48	16:81089551:A:G
Adipose Subcutaneous	eqtl	6.1e-24	-0.27	16:81137136:G:A
Skin Sun Exposed Lower leg	eqtl	8.0e-23	-0.47	16:81080067:C:T
Thyroid	eqtl	1.9e-21	+0.45	16:81103437:T:C
Cells Cultured fibroblasts	eqtl	2.0e-21	-0.26	16:81080110:G:C
Adipose Visceral Omentum	eqtl	2.0e-18	-0.23	16:81137136:G:A
Muscle Skeletal	eqtl	1.6e-15	-0.26	16:81084661:C:T
Brain Caudate basal ganglia	eqtl	1.8e-15	+0.46	16:81095370:C:T
Heart Left Ventricle	eqtl	4.0e-14	-0.38	16:81097740:C:G
Brain Putamen basal ganglia	eqtl	6.3e-14	+0.44	16:81095811:G:A
Brain Frontal Cortex BA9	eqtl	9.7e-13	+0.40	16:81096889:A:G
Brain Cortex	eqtl	5.1e-12	+0.44	16:81093378:T:C
Brain Anterior cingulate cortex BA24	eqtl	2.0e-11	+0.44	16:81095811:G:A
Esophagus Mucosa	eqtl	3.0e-11	-0.32	16:81083175:TAA:T
Brain Nucleus accumbens basal ganglia	eqtl	1.9e-10	+0.37	16:81095370:C:T
Brain Cerebellum	eqtl	4.2e-09	+0.55	16:81095811:G:A
Heart Atrial Appendage	eqtl	1.8e-08	-0.33	16:81031677:C:T
Artery Aorta	eqtl	2.5e-08	-0.33	16:81031677:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
158271	8.0694	1723
158270	2.0371	1012
207978	1.0393	622

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.32	gold quality
substantia nigra	UBERON:0002038	98.22	gold quality
amygdala	UBERON:0001876	98.08	gold quality
temporal lobe	UBERON:0001871	98.02	gold quality
putamen	UBERON:0001874	97.87	gold quality
hypothalamus	UBERON:0001898	97.69	gold quality
Ammon’s horn	UBERON:0001954	97.56	gold quality
caudate nucleus	UBERON:0001873	97.43	gold quality
nucleus accumbens	UBERON:0001882	97.32	gold quality
ventricular zone	UBERON:0003053	97.01	gold quality
right lobe of liver	UBERON:0001114	96.61	gold quality
anterior cingulate cortex	UBERON:0009835	96.20	gold quality
primary visual cortex	UBERON:0002436	96.06	gold quality
cerebral cortex	UBERON:0000956	96.02	gold quality
ganglionic eminence	UBERON:0004023	95.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.85	gold quality
left lobe of thyroid gland	UBERON:0001120	95.75	gold quality
thyroid gland	UBERON:0002046	95.73	gold quality
right frontal lobe	UBERON:0002810	95.73	gold quality
frontal cortex	UBERON:0001870	95.58	gold quality
corpus callosum	UBERON:0002336	95.58	gold quality
prefrontal cortex	UBERON:0000451	95.56	gold quality
endometrium	UBERON:0001295	95.49	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.49	gold quality
liver	UBERON:0002107	95.40	gold quality
brain	UBERON:0000955	95.19	gold quality
right lobe of thyroid gland	UBERON:0001119	95.19	gold quality
adult mammalian kidney	UBERON:0000082	95.11	gold quality
superior frontal gyrus	UBERON:0002661	94.64	gold quality
placenta	UBERON:0001987	94.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.42	gold quality
gastrocnemius	UBERON:0001388	93.92	gold quality
muscle of leg	UBERON:0001383	93.85	gold quality
kidney	UBERON:0002113	93.40	gold quality
cortex of kidney	UBERON:0001225	93.13	gold quality
cortical plate	UBERON:0005343	92.93	gold quality
skeletal muscle tissue	UBERON:0001134	92.92	gold quality
metanephros cortex	UBERON:0010533	92.62	gold quality
heart left ventricle	UBERON:0002084	92.52	gold quality
muscle tissue	UBERON:0002385	91.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.69	gold quality
omental fat pad	UBERON:0010414	91.33	gold quality
heart	UBERON:0000948	91.21	gold quality
body of pancreas	UBERON:0001150	91.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.12	gold quality
tibial nerve	UBERON:0001323	91.09	gold quality
cerebellar cortex	UBERON:0002129	90.94	gold quality
cerebellar hemisphere	UBERON:0002245	90.89	gold quality
thoracic mammary gland	UBERON:0005200	90.88	gold quality
adipose tissue	UBERON:0001013	90.77	gold quality
cerebellum	UBERON:0002037	90.77	gold quality
right adrenal gland cortex	UBERON:0035827	90.28	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.22	gold quality
left coronary artery	UBERON:0001626	90.06	gold quality
adrenal tissue	UBERON:0018303	89.89	gold quality
fallopian tube	UBERON:0003889	89.84	gold quality
pancreas	UBERON:0001264	89.76	gold quality
right adrenal gland	UBERON:0001233	89.68	gold quality
left adrenal gland	UBERON:0001234	89.59	gold quality
adenohypophysis	UBERON:0002196	89.56	gold quality
left adrenal gland cortex	UBERON:0035825	89.55	gold quality
adrenal gland	UBERON:0002369	89.54	gold quality
right atrium auricular region	UBERON:0006631	89.22	gold quality
prostate gland	UBERON:0002367	89.17	gold quality
ovary	UBERON:0000992	89.08	gold quality
tibial artery	UBERON:0007610	89.02	gold quality
popliteal artery	UBERON:0002250	89.01	gold quality
right ovary	UBERON:0002118	88.95	gold quality
calcaneal tendon	UBERON:0003701	88.89	gold quality
left ovary	UBERON:0002119	88.78	gold quality
apex of heart	UBERON:0002098	88.76	gold quality
islet of Langerhans	UBERON:0000006	88.64	gold quality
smooth muscle tissue	UBERON:0001135	88.51	gold quality
pituitary gland	UBERON:0000007	88.28	gold quality
rectum	UBERON:0001052	88.15	gold quality
ectocervix	UBERON:0012249	88.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.00	gold quality
multicellular organism	UBERON:0000468	87.86	gold quality
left uterine tube	UBERON:0001303	87.86	gold quality
descending thoracic aorta	UBERON:0002345	87.58	gold quality
mucosa of stomach	UBERON:0001199	87.47	gold quality
thoracic aorta	UBERON:0001515	87.36	gold quality
saliva-secreting gland	UBERON:0001044	87.35	gold quality
ascending aorta	UBERON:0001496	87.34	gold quality
right coronary artery	UBERON:0001625	87.15	gold quality
body of stomach	UBERON:0001161	87.14	gold quality
gall bladder	UBERON:0002110	87.04	gold quality
endocervix	UBERON:0000458	87.03	gold quality
minor salivary gland	UBERON:0001830	87.03	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.03	gold quality
esophagus	UBERON:0001043	86.85	gold quality
esophagus mucosa	UBERON:0002469	86.81	gold quality
fundus of stomach	UBERON:0001160	86.76	gold quality
lower esophagus	UBERON:0013473	86.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.74	gold quality
vagina	UBERON:0000996	86.73	gold quality
uterine cervix	UBERON:0000002	86.51	gold quality
urinary bladder	UBERON:0001255	86.36	gold quality
tonsil	UBERON:0002372	86.26	gold quality
stromal cell of endometrium	CL:0002255	86.13	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1166.26
E-HCAD-5	yes	33.96
E-GEOD-134144	yes	33.63
E-HCAD-10	yes	18.74
E-MTAB-6678	yes	16.08
E-MTAB-10042	yes	14.71
E-GEOD-93593	yes	14.16
E-ANND-3	yes	10.38
E-CURD-112	yes	9.86
E-MTAB-8271	yes	8.20
E-MTAB-8060	no	786.26
E-MTAB-9689	no	458.99
E-CURD-114	no	17.83

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	111.1	high
Thyroid gland	tissue	90.4	high
Kidney	tissue	72.9	high
Frontal cortex	tissue	65.6
Epididymis	tissue	64.9	high
Caudate putamen	tissue	62.7
Tongue	tissue	59.3
Spinal cord	tissue	56.3
Pons	tissue	48.9
Substantia nigra	tissue	46.7
Thalamus	tissue	46.6
Midbrain	tissue	46.1
Medulla oblongata	tissue	45.0
Superior colliculi	tissue	40.6
Skeletal muscle	tissue	38.4	medium
Amygdala	tissue	38.3
Hypothalamus	tissue	38.2
Septum	tissue	37.9
Hippocampal formation	tissue	37.0
Putamen	tissue	36.4
Periaqueductal gray	tissue	36.0
Cerebral cortex	tissue	35.9	high
Nucleus accumbens	tissue	35.9
Somatosensory cortex	tissue	35.9
Locus coeruleus	tissue	35.7
Motor cortex	tissue	35.2
Occipital cortex	tissue	35.0
Entorhinal cortex	tissue	34.4
Temporal cortex	tissue	34.2
Ventral forebrain	tissue	34.1
Hippocampus	tissue	33.8	high
Prefrontal cortex	tissue	33.6
Retrosplenial and cingulate cortex	tissue	32.6
Retrosplenial cortex	tissue	32.3
Insular cortex	tissue	30.4
Parathyroid gland	tissue	29.2	high
Postcentral gyrus	tissue	29.0
Basal ganglia	tissue	28.7	high
Corpus callosum	tissue	28.2
Olfactory bulb	tissue	26.2
Choroid plexus	tissue	26.0
Cerebellum	tissue	25.0	high
Placenta	tissue	24.4	high
Heart muscle	tissue	22.7	high
Adipose tissue	tissue	21.9	medium
Breast	tissue	20.5	high
Ovary	tissue	19.1	high
Fallopian tube	tissue	18.6	high
Adrenal gland	tissue	17.9	high
Prostate	tissue	17.6	high
Cervix	tissue	17.1	high
Endometrium 1	tissue	16.4	high
Seminal vesicle	tissue	15.8	high
Vagina	tissue	14.7	high
Retina	tissue	14.4
Pituitary gland	tissue	14.0
Urinary bladder	tissue	13.5	high
Salivary gland	tissue	13.4	high
Rectum	tissue	12.2	high
Colon	tissue	11.7	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar white matter (59.9), Globus pallidus, externus (58.2), Globus pallidus, internus (57.8), Red nucleus (57.8), Ventral spinal cord (56.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, JUN

miRNA regulators (miRDB)

Targeting GCSH by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 60 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-7154-5P	99.69	70.52	1900

Functional genomics

gnomAD constraint: pLI 0.334, LOEUF 1.54, missense Z -1.11 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000315467 — one region, missense o/e 0.82. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 39.5% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SU-DHL-5 (-1.591), PF-382 (-1.534), RS4;11 (-1.312), SU-DHL-1 (-1.304), OCI-AML2 (-1.288), NCI-H526 (-1.249), TOV-21G (-1.238), F-36P (-1.219), NALM-6 (-1.148), MC116 (-1.144), KMS-27 (-1.136), NCI-H157-DM (-1.132), SEM (-1.121), NCI-H1703 (-1.115), NCI-H441 (-1.089).

Literature-anchored findings (GeneRIF, showing 7)

• Heterozygous GCSH gene mutation in transient neonatal hyperglycinemia. (PMID:12402263)
• Genetic analysis showed a non-previously described mutation affecting a consensus splice site (IVS2-1G > C 3) in the AMT gene encoding the T protein of the glycine cleavage system. (PMID:19299230)
• There is no detectable glycine cleavage enzyme activity in human skin fibroblasts. (PMID:21539457)
• Data indicate no mutation was found in glycine cleavage system protein-H (GCSH) and suggest that mutations in both glycine decarboxylase (GLDC) and aminomethyltransferase (AMT) are the main cause of glycine encephalopathy in Malaysian population. (PMID:25231368)
• GCSH protein is overexpressed in both, breast cancer tissue and breast cancer cell lines. A shorter (391 bp) transcript variant (Tv*) was amplified with an increased expression in healthy breast cells and a decreased expression in breast cancer samples. A GCSH-equilibrium at the transcript level is likely conceivable for optimal glycine degradation. (PMID:30337557)
• Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia. (PMID:33890291)
• Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency. (PMID:36190515)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gcsh	ENSMUSG00000034424
rattus_norvegicus	Gcsh	ENSRNOG00000011535
rattus_norvegicus	Gcshl1	ENSRNOG00000051496
rattus_norvegicus	AABR07067762.1	ENSRNOG00000055383
rattus_norvegicus		ENSRNOG00000069283
drosophila_melanogaster	ppl	FBGN0027945
caenorhabditis_elegans		WBGENE00008354
caenorhabditis_elegans	gcsh-2	WBGENE00009918

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1915383) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 12 distinct phenotype terms.

Mouse phenotype (MP)	Records
preweaning lethality, complete penetrance	2
decreased embryo size	1
embryonic growth arrest	1
abnormal embryonic tissue morphology	1
increased mean corpuscular volume	1
increased basophil cell number	1
increased mean corpuscular hemoglobin	1
absent somites	1
prolonged RR interval	1
embryonic lethality between implantation and placentation, incomplete penetrance	1
absent neural folds	1
embryonic lethality prior to organogenesis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Leptospira borgpetersenii serovar Hardjo-bovis str. JB197	Q04PM8	100.0%	Diamond
Leptospira borgpetersenii serovar Hardjo-bovis str. L550	Q055P7	100.0%	Diamond
Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130	Q72VI7	100.0%	Diamond
Leptospira interrogans serovar Lai str. 56601	Q8F936	100.0%	Diamond
Flaveria pringlei	P49359	98.8%	Diamond
Flaveria anomala	Q39732	98.8%	Diamond
Flaveria pubescens	P49360	98.7%	Diamond
Arabidopsis thaliana	P25855	93.4%	Diamond
Flaveria trinervia	P46485	92.0%	Diamond
Bartonella quintana str. Toulouse	Q6FYZ6	91.8%	Diamond
Bartonella henselae str. Houston-1	Q6G2F0	91.8%	Diamond
Oryctolagus cuniculus	Q9N121	91.3%	Diamond
Bos taurus	P20821	89.6%	Diamond
Bartonella tribocorum CIP 105476	A9IWV1	86.9%	Diamond
Gallus gallus	P11183	79.7%	Diamond
Bartonella bacilliformis KC583	A1UTQ4	78.7%	Diamond
Xanthobacter versatilis	A7IHF1	69.4%	Diamond
Parvibaculum lavamentivorans DS-1	A7HQX9	65.6%	Diamond
Rhodospirillum rubrum ATCC 11170	Q2RPV0	65.6%	Diamond
Paramagnetospirillum magneticum AMB-1	Q2W9A4	63.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9HDV9	55.7%	Diamond
Saccharomyces cerevisiae S288C	P39726	52.6%	Diamond
Dictyostelium discoideum	Q54FI0	44.3%	Diamond
Aquifex aeolicus VF5	O67151	40.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CENPN-AS1	ncRNA	107984858
PKD1L2	protein-coding	114780
C16orf46	protein-coding	123775
ATMIN	protein-coding	23300
CENPN	protein-coding	55839
MIR4720	ncRNA	100616150
C16orf46-AS1	ncRNA	105371361
BCO1	protein-coding	53630
GAN	protein-coding	8139
ARLNC1	ncRNA	100996425
CMC2	protein-coding	56942
CMIP	protein-coding	80790

Protein

Protein identifiers

Glycine cleavage system H protein, mitochondrial — P23434 (reviewed: P23434)

Alternative names: Lipoic acid-containing protein

All UniProt accessions (9): A0A1W2PNX3, A0A1W2PQV2, A0A1W2PQX3, P23434, H3BNV1, H3BPF0, H3BQ30, H3BUG8, H3BUH9

UniProt curated annotations — full annotation on UniProt →

Function. The glycine cleavage system catalyzes the degradation of glycine. The H protein (GCSH) shuttles the methylamine group of glycine from the P protein (GLDC) to the T protein (GCST). Has a pivotal role in the lipoylation of enzymes involved in cellular energetics such as the mitochondrial dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex (DLAT), and the mitochondrial dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex (DLST).

Subunit / interactions. Interacts with GLDC. The glycine cleavage system is composed of four proteins: P (GLDC), T (GCST), L (DLD) and H (GCSH).

Subcellular location. Mitochondrion.

Disease relevance. Multiple mitochondrial dysfunctions syndrome 7 (MMDS7) [MIM:620423] An autosomal recessive disorder biochemically characterized by glycine accumulation in body fluids, including the cerebrospinal fluid, with an elevated cerebrospinal fluid/plasma glycine ratio. The broad clinical spectrum ranges from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, limited verbal communication, behavioral problems, seizures and variable movement problems. Death in infancy or early childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 lipoyl cofactor covalently.

Similarity. Belongs to the GcvH family.

RefSeq proteins (1): NP_004474* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR002930	GCV_H	Family
IPR003016	2-oxoA_DH_lipoyl-BS	Binding_site
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR017453	GCV_H_sub	Family
IPR033753	GCV_H/Fam206	Family

Pfam: PF01597

Enzyme classification (BRENDA)

• EC 1.4.1.27 — glycine cleavage system (BRENDA: 15 organisms, 4 substrates, 5 inhibitors, 6 Km, 0 kcat entries)
• EC 1.4.4.2 — glycine dehydrogenase (aminomethyl-transferring) (BRENDA: 25 organisms, 27 substrates, 22 inhibitors, 32 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCINE	0.0003–40	19
GLYCINE	6.6–40	2
TETRAHYDROFOLATE	0.05–0.17	2
LIPOYLATED H-APOPROTEIN	0.47–12.3	2
LIPOYLATED HIS-TAGGED H-APOPROTEIN	1–12.6	2
LIPOIC ACID	0.83	1
BICARBONATE	31	1
CO2	3.4	1
H1 PROTEIN	0.0026	1
H2 PROTEIN	0.0037	1
HIS-TAGGED H-APOPROTEIN	12.3	1
LIPOAMIDE	0.043	1
PYRIDOXAL 5’-PHOSPHATE	0.0046	1
RTVH1 PROTEIN	0.0026	1
RTVH2 PROTEIN	0.0037	1

UniProt features (23 total): strand 7, sequence variant 6, helix 5, transit peptide 1, chain 1, turn 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
8UGO	Structure of the complex between Human LIAS and H-protein in the presence of …	X-RAY DIFFRACTION	2.45
8V0J	Structure of the complex between Human LIAS and H-protein in the presence of …	X-RAY DIFFRACTION	2.58
9C19	Structure of human LIAS	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23434-F1	85.49	0.71

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH supported · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1)

Type	Positions
N6-lipoyllysine	107

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-6783984	Glycine degradation	curated
R-HSA-9857492	Protein lipoylation	curated
R-HSA-389661	Glyoxylate metabolism and glycine degradation	—
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 315 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, SHEPARD_BMYB_MORPHOLINO_UP, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, USF_C, PRAMOONJAGO_SOX4_TARGETS_DN, PUJANA_CHEK2_PCC_NETWORK, SCHUHMACHER_MYC_TARGETS_UP, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, MYCMAX_01, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_GLYCINE_METABOLIC_PROCESS

GO Biological Process (1): glycine decarboxylation via glycine cleavage system (GO:0019464)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), glycine cleavage complex (GO:0005960)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Glyoxylate metabolism and glycine degradation	1
Post-translational protein modification	1
Metabolism of amino acids and derivatives	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

8 GO namespaces:

Category	Terms
glycine catabolic process	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
oxidoreductase complex	1
transferase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 5 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
mitochondrion	CC	high-throughput

Protein interactions and networks

STRING

showing 15 of 1,526 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCSH	GLDC	P23378	981
GCSH	AMT	P48728	974
GCSH	LIPT1	Q9Y234	971
GCSH	MYBPH	Q13203	951
GCSH	DLAT	P10515	922
GCSH	OCA2	Q04671	844
GCSH	LIPT2	A6NK58	833
GCSH	LIAS	O43766	827
GCSH	FDX1	P10109	774
GCSH	SLC31A1	O15431	758
GCSH	PDHB	P11177	757
GCSH	ATP7B	P35670	740
GCSH	PDHA1	P08559	723
GCSH	DLD	P09622	711
GCSH	ATP7A	Q04656	675

IntAct

Human interaction partners of GCSH in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
NMI	physical association	0.670	4
CIDEB	physical association	0.560	3
MAGEA11	physical association	0.560	3
MAGEA6	physical association	0.560	3
MED11	physical association	0.560	3
MIS18A	physical association	0.560	3
RHBDD2	physical association	0.560	3
LIAS	association	0.530	2
ING5	physical association	0.000	1
ZBTB16	physical association	0.000	1

BioGRID (63 interactions; top human partners by supporting records): NMI (Two-hybrid; 3 records), ACO2 (Co-fractionation), ACSF2 (Co-fractionation), ADPRHL2 (Co-fractionation), ARCN1 (Co-fractionation), C9orf142 (Affinity Capture-MS), CIDEB (Two-hybrid), CLIC1 (Co-fractionation), CLIC4 (Co-fractionation), CMPK1 (Co-fractionation), COA7 (Co-fractionation), CPOX (Co-fractionation), EGFR (Negative Genetic), ENO1 (Co-fractionation), FASN (Negative Genetic)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
GCSH	“form complex”	“Glycine cleavage system”	binding

Disease & clinical

Genetic variants

Variant evidence for GCSH: 161 ClinVar records (13 pathogenic / likely pathogenic); 6 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

161 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	6
Uncertain significance	72
Likely benign	32
Benign	29

Top pathogenic / likely-pathogenic (13)

Showing all 13 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1000783	NM_004483.5(GCSH):c.338_342del (p.Tyr113fs)	Pathogenic	criteria provided, single submitter	1
4081417	NM_004483.5(GCSH):c.317_318del (p.Val106fs)	Likely pathogenic	criteria provided, single submitter	1
4819634	NM_004483.5(GCSH):c.380T>C (p.Leu127Pro)	Likely pathogenic	criteria provided, single submitter	1
4850296	NM_004483.5(GCSH):c.43_53del (p.Thr15fs)	Likely pathogenic	criteria provided, single submitter	1
4880621	NM_004483.5(GCSH):c.70dup (p.Ala24fs)	Likely pathogenic	criteria provided, single submitter	1
4974972	NM_004483.5(GCSH):c.1_2del (p.Met1fs)	Likely pathogenic	criteria provided, single submitter	1
832058	NC_000016.10:g.(?81082846)(81096298_?)del	Pathogenic	criteria provided, single submitter	1
1023159	NC_000016.9:g.(?81121196)(81129883_?)del	Pathogenic	criteria provided, single submitter	1
2506439	NM_004483.5(GCSH):c.170A>G (p.His57Arg)	Pathogenic	no assertion criteria provided	1
2506440	NG_016427.1:g.(5246_10695)_(10776_13711)del	Pathogenic	no assertion criteria provided	1
2506441	NM_004483.5(GCSH):c.293-60_*72dup	Pathogenic	no assertion criteria provided	1
2506442	NM_004483.5(GCSH):c.344C>T (p.Pro115Leu)	Pathogenic	no assertion criteria provided	1
56415	NM_004483.5(GCSH):c.425-1G>T	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore GCSH’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 655):

Position(s)	Effect	Δscore	Sites
16:81082964	acceptor_loss	1.0000
16:81084461–81084462	donor_loss	1.0000	6
16:81084596	acceptor_loss	1.0000	3
16:81084599	acceptor_gain	1.0000
16:81087665–81087666	acceptor_loss	1.0000	6
16:81090681–81090682	acceptor_loss	1.0000	6
16:81091337	donor_gain	1.0000
16:81082964–81082965	acceptor_loss	0.9900	4
16:81084595	acceptor_loss	0.9900
16:81087599–81087600	donor_loss	0.9900	5

AlphaMissense

448 missense substitutions predicted likely pathogenic (of 1,101 scored), across 99 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H57	8	0.991	0.996
S105	8	0.984	0.999
D81	8	0.970	0.995
N135	8	0.968	0.997
F100	8	0.918	0.994
S110	8	0.916	0.998
E104	7	0.997	0.999
F53	7	0.992	0.999
K107	7	0.992	1.000
W143	7	0.992	0.998
W59	7	0.989	0.999
F74	7	0.989	0.999
E58	7	0.985	0.996
S72	7	0.974	0.999
C85	7	0.960	0.997
E111	7	0.950	0.993
N124	7	0.946	0.991
Q76	7	0.925	0.998
C138	7	0.922	0.989
M159	7	0.886	0.970

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	2.76e-05
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000927

Disease associations

OMIM: gene MIM:238330 | disease phenotypes: MIM:605899, MIM:620423

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
multiple mitochondrial dysfunctions syndrome 7	Strong	Autosomal recessive	4
neonatal glycine encephalopathy	Supportive	Autosomal recessive
infantile glycine encephalopathy	Supportive	Autosomal recessive
atypical glycine encephalopathy	Supportive	Unknown
glycine encephalopathy	Limited	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 7	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
DDG2P	green
Early onset or syndromic epilepsy	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (5): glycine encephalopathy (MONDO:0011612), multiple mitochondrial dysfunctions syndrome 7 (MONDO:0957382), neonatal glycine encephalopathy (MONDO:0017353), infantile glycine encephalopathy (MONDO:0017354), atypical glycine encephalopathy (MONDO:0015010)

Orphanet (1): Glycine encephalopathy (Orphanet:407)

HPO phenotypes

55 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000194	Open mouth
HP:0000212	Gingival overgrowth
HP:0000268	Dolichocephaly
HP:0000463	Anteverted nares
HP:0000713	Agitation
HP:0000729	Autistic behavior
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000752	Hyperactivity
HP:0000961	Cyanosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001410	Decreased liver function
HP:0001873	Thrombocytopenia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002033	Poor suck
HP:0002079	Hypoplasia of the corpus callosum
HP:0002104	Apnea
HP:0002154	Hyperglycinemia
HP:0002267	Exaggerated startle response
HP:0002521	Hypsarrhythmia
HP:0003074	Hyperglycemia
HP:0003228	Hypernatremia
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004887	Respiratory failure requiring assisted ventilation
HP:0005484	Secondary microcephaly
HP:0007359	Focal-onset seizure
HP:0008936	Axial hypotonia
HP:0010851	EEG with burst suppression
HP:0011448	Ankle clonus
HP:0011577	Partial atrioventricular canal defect
HP:0011968	Feeding difficulties
HP:0012469	Infantile spasms
HP:0012707	Elevated brain lactate level by MRS
HP:0012708	Reduced brain N-acetyl aspartate level by MRS
HP:0031165	Multifocal seizures
HP:0032615	Abnormal diffusion weighted cerebral MRI morphology
HP:0032794	Myoclonic seizure
HP:0033725	Thin corpus callosum
HP:0034893	Elevated brain glycine level by MRS
HP:0100247	Recurrent singultus
HP:0100710	Impulsivity
HP:0500230	Increased CSF glycine concentration

GWAS associations

6 associations:

Study	Trait	p-value
GCST007638_50	Glycine levels	1e-41
GCST007836_12	Glycine levels	4e-31
GCST007838_9	Glycine levels	1e-18
GCST007837_7	Glycine levels	7e-15
GCST005962_55	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1e-6
GCST005958_4	Waist-to-hip ratio adjusted for BMI (age >50)	4e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009767	glycine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Glycine recycling

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, increases abundance	3
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	decreases expression	1
MT19c compound	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Fluorouracil	affects reaction, decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Methotrexate	affects response to substance	1
Methyl Methanesulfonate	decreases expression	1
Phenobarbital	affects expression	1
Piroxicam	decreases expression	1
Plant Extracts	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

3 trials:

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan