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): 151 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 55
• Cancer dependency (DepMap): dependent in 39.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• 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: 15 — 12 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000315467, ENST00000561801, ENST00000564386, ENST00000564477, ENST00000566566, ENST00000569885, ENST00000639137, ENST00000639169, ENST00000639689, ENST00000640150, ENST00000879489, ENST00000879490, ENST00000879491, ENST00000879492, ENST00000879493

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.

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

134 total, 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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, JUN

miRNA regulators (miRDB)

60 targeting GCSH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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.

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

Protein

Protein identifiers

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

Alternative names: Lipoic acid-containing protein

All UniProt accessions (9): P23434, A0A1W2PNX3, A0A1W2PQV2, A0A1W2PQX3, 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 (10 total): sequence variant 6, transit peptide 1, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8UGO	X-RAY DIFFRACTION	2.45
8V0J	X-RAY DIFFRACTION	2.58
9C19	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

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

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): 107

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6783984	Glycine degradation
R-HSA-9857492	Protein lipoylation

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 (2): glycine decarboxylation via glycine cleavage system (GO:0019464), glycine catabolic process (GO:0006546)

GO Molecular Function (2): aminomethyltransferase activity (GO:0004047), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glyoxylate metabolism and glycine degradation	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycine catabolic process	1
glycine metabolic process	1
amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
hydroxymethyl-, formyl- and related transferase activity	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
oxidoreductase complex	1
transferase complex	1

Protein interactions and networks

STRING

1982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCSH	GLDC	P23378	993
GCSH	AMT	P48728	991
GCSH	MYBPH	Q13203	957
GCSH	OCA2	Q04671	943
GCSH	LIPT1	Q9Y234	940
GCSH	DLD	P09622	860
GCSH	DLAT	P10515	802
GCSH	LIPT2	A6NK58	664
GCSH	LIAS	O43766	636
GCSH	SHMT1	P34896	609
GCSH	SHMT2	P34897	567
GCSH	ADCY10	Q96PN6	567
GCSH	KYAT3	Q6YP21	548
GCSH	MTHFD1	P11586	540
GCSH	C16orf46	Q6P387	539
GCSH	ELOF1	P60002	539

IntAct

34 interactions, top by confidence:

A	B	Type	Score
GCSH	NMI	psi-mi:“MI:0915”(physical association)	0.670
NMI	GCSH	psi-mi:“MI:0915”(physical association)	0.670
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
GCSH	MAGEA6	psi-mi:“MI:0915”(physical association)	0.560
GCSH	MIS18A	psi-mi:“MI:0915”(physical association)	0.560
GCSH	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
GCSH	MED11	psi-mi:“MI:0915”(physical association)	0.560
GCSH	MAGEA11	psi-mi:“MI:0915”(physical association)	0.560
GCSH	RHBDD2	psi-mi:“MI:0915”(physical association)	0.560
GCSH	LIAS	psi-mi:“MI:0914”(association)	0.530
	CYB5B	psi-mi:“MI:0914”(association)	0.500
PPM1K	PMPCB	psi-mi:“MI:0914”(association)	0.350
IGF2BP3	NDUFA3	psi-mi:“MI:0914”(association)	0.350
MMGT1	SAP18	psi-mi:“MI:0914”(association)	0.350
LIAS	HMGN4	psi-mi:“MI:0914”(association)	0.350
GCSH	MAGEA11	psi-mi:“MI:0915”(physical association)	0.000
GCSH	NMI	psi-mi:“MI:0915”(physical association)	0.000
GCSH	MAGEA6	psi-mi:“MI:0915”(physical association)	0.000
GCSH	MIS18A	psi-mi:“MI:0915”(physical association)	0.000
GCSH	CIDEB	psi-mi:“MI:0915”(physical association)	0.000
GCSH	MED11	psi-mi:“MI:0915”(physical association)	0.000
GCSH	RHBDD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (63): NMI (Two-hybrid), SFI1 (Two-hybrid), NMI (Two-hybrid), GCSH (Co-fractionation), GCSH (Co-fractionation), GCSH (Co-fractionation), PSMB5 (Co-fractionation), NUDT9 (Co-fractionation), TPI1 (Co-fractionation), GCSH (Co-fractionation), GCSH (Co-fractionation), CPOX (Co-fractionation), GCSH (Co-fractionation), FDX1L (Co-fractionation), GSTO1 (Co-fractionation)

ESM2 similar proteins: A0A8I5ZNK2, A1YFX9, A6QLH6, B0BNF8, D3ZAW2, O43502, O88600, P08760, P11183, P20821, P23434, P27465, P33124, P34932, P97679, Q28DS0, Q28G67, Q29S16, Q2KIK0, Q2TFN9, Q571F8, Q5I0K3, Q5I0P2, Q5NVK4, Q5R8I8, Q5RDM4, Q5RFI8, Q5RFS0, Q5ZHW7, Q61316, Q6GR35, Q80ZQ9, Q86WA6, Q8BSF4, Q8JGT5, Q8K1Z0, Q8N0X4, Q8R2J9, Q8R4N0, Q91WC3

Diamond homologs: A1AF93, A1UTQ4, A4WE56, A5FUJ7, A5IR11, A6TZT7, A6U8Q4, A7HQX9, A7IHF1, A7MR83, A7X019, A7ZR13, A8A445, A8APB3, A8LIH3, A9IWV1, A9KC18, A9MRH1, A9N3N2, A9NA78, A9W103, B0K241, B0KD96, B0UAJ5, B1IT98, B1LDA4, B1XEJ1, B1Z7Y5, B2IGK2, B2U0S1, B3PP19, B4RF17, B4T549, B4TGX4, B4TV23, B5BFL9, B5F5H9, B5FUG7, B5QXI1, B5RE15

SIGNOR signaling

1 interactions.

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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	71
Likely benign	26
Benign	30

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1000783	NM_004483.5(GCSH):c.338_342del (p.Tyr113fs)	Pathogenic
1023159	NC_000016.9:g.(?81121196)(81129883_?)del	Pathogenic
2506439	NM_004483.5(GCSH):c.170A>G (p.His57Arg)	Pathogenic
2506440	NG_016427.1:g.(5246_10695)_(10776_13711)del	Pathogenic
2506441	NM_004483.5(GCSH):c.293-60_*72dup	Pathogenic
2506442	NM_004483.5(GCSH):c.344C>T (p.Pro115Leu)	Pathogenic
832058	NC_000016.10:g.(?81082846)(81096298_?)del	Pathogenic
4081417	NM_004483.5(GCSH):c.317_318del (p.Val106fs)	Likely pathogenic
4819634	NM_004483.5(GCSH):c.380T>C (p.Leu127Pro)	Likely pathogenic
56415	NM_004483.5(GCSH):c.425-1G>T	Likely pathogenic

SpliceAI

1051 predictions. Top by Δscore:

Variant	Effect	Δscore
16:81082959:CCAAC:C	acceptor_gain	1.0000
16:81082960:CAACC:C	acceptor_gain	1.0000
16:81082961:AACC:A	acceptor_loss	1.0000
16:81082962:ACCT:A	acceptor_loss	1.0000
16:81082964:C:CC	acceptor_gain	1.0000
16:81084420:A:AC	donor_gain	1.0000
16:81084421:C:CC	donor_gain	1.0000
16:81084457:GCTTA:G	donor_loss	1.0000
16:81084458:CTTAC:C	donor_loss	1.0000
16:81084460:T:TG	donor_loss	1.0000
16:81084461:A:AC	donor_gain	1.0000
16:81084462:C:CC	donor_gain	1.0000
16:81084462:C:CG	donor_loss	1.0000
16:81084462:CCAT:C	donor_gain	1.0000
16:81084590:CTCAT:C	acceptor_gain	1.0000
16:81084591:TCAT:T	acceptor_gain	1.0000
16:81084592:CAT:C	acceptor_gain	1.0000
16:81084592:CATC:C	acceptor_gain	1.0000
16:81084593:AT:A	acceptor_gain	1.0000
16:81084594:TCT:T	acceptor_loss	1.0000
16:81084595:C:CC	acceptor_gain	1.0000
16:81084595:CTA:C	acceptor_loss	1.0000
16:81084599:G:C	acceptor_gain	1.0000
16:81084599:G:GC	acceptor_gain	1.0000
16:81087663:TCCTA:T	acceptor_loss	1.0000
16:81087665:C:T	acceptor_loss	1.0000
16:81087666:T:G	acceptor_loss	1.0000
16:81090677:CGCA:C	acceptor_gain	1.0000
16:81090679:CA:C	acceptor_gain	1.0000
16:81090680:AC:A	acceptor_loss	1.0000

AlphaMissense

1101 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:81084566:T:A	K107N	1.000
16:81084566:T:G	K107N	1.000
16:81084567:T:A	K107I	1.000
16:81084561:G:T	A109D	0.999
16:81084564:G:T	A108D	0.999
16:81084565:C:G	A108P	0.999
16:81084568:T:C	K107E	0.999
16:81084568:T:G	K107Q	0.999
16:81084572:A:C	S105R	0.999
16:81084572:A:T	S105R	0.999
16:81084574:T:G	S105R	0.999
16:81084577:C:T	E104K	0.999
16:81084585:C:T	G101D	0.999
16:81087645:A:T	V83D	0.999
16:81087654:C:A	G80V	0.999
16:81087654:C:T	G80E	0.999
16:81087661:C:G	A78P	0.999
16:81090605:G:T	A75E	0.999
16:81090607:A:C	F74L	0.999
16:81090607:A:T	F74L	0.999
16:81090609:A:G	F74L	0.999
16:81090613:G:C	S72R	0.999
16:81090613:G:T	S72R	0.999
16:81090615:T:G	S72R	0.999
16:81090620:C:T	G70E	0.999
16:81090654:A:G	W59R	0.999
16:81090654:A:T	W59R	0.999
16:81090670:G:C	F53L	0.999
16:81090670:G:T	F53L	0.999
16:81090672:A:G	F53L	0.999

dbSNP variants (sampled 300 via entrez): RS1000023343 (16:81096242 G>C), RS1000086777 (16:81096409 G>A,C,T), RS1000140161 (16:81086319 G>A), RS1000708632 (16:81088988 C>T), RS1001027994 (16:81096685 G>A), RS1001170524 (16:81095568 G>C), RS1001177871 (16:81083962 T>C), RS1001220839 (16:81091600 T>C), RS1001233735 (16:81094728 T>A), RS1001273315 (16:81091779 T>C), RS1001578108 (16:81081803 T>A,G), RS1001819795 (16:81096029 T>C), RS1001913967 (16:81096542 G>A,C), RS1002034688 (16:81093131 A>C), RS1002156107 (16:81088172 C>A,T)

Disease associations

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

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 7	Strong	Autosomal recessive
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 (1)

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

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 7	Definitive	AR

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 total (30 of 55 shown, 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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005958_20	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_30	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-06
GCST007638_48	Glycine levels	1.000000e-41
GCST007836_12	Glycine levels	4.000000e-31
GCST007837_7	Glycine levels	7.000000e-15
GCST007838_10	Glycine levels	1.000000e-18

EFO canonical traits (4, from GWAS)

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 (VIP=true, CPIC=false)

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	decreases expression, increases abundance, increases expression	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	increases abundance, decreases expression	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)

3 trials via MONDO — disease-level, not drug-specific.

Trial	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