Multiple mitochondrial dysfunctions syndrome 7

disease

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Also known as GCSH-related glycine encephalopathy

Summary

Multiple mitochondrial dysfunctions syndrome 7 (MONDO:0957382) is a disease caused by GCSH (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: GCSH (GenCC Strong)
Cohort genes: 1
ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 7
Mondo ID	MONDO:0957382
OMIM	620423
UMLS	C5830586
MedGen	1841222
GARD	0026818
Is cancer (heuristic)	no

Also known as: GCSH-related glycine encephalopathy

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › glycine encephalopathy › multiple mitochondrial dysfunctions syndrome 7

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

11 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 pathogenic/likely pathogenic, 2 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506436	NM_004483.5(GCSH):c.293-2_293-1insT	GCSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506439	NM_004483.5(GCSH):c.170A>G (p.His57Arg)	GCSH	Pathogenic	no assertion criteria provided
2506440	NG_016427.1:g.(5246_10695)_(10776_13711)del	GCSH	Pathogenic	no assertion criteria provided
2506441	NM_004483.5(GCSH):c.293-60_*72dup	GCSH	Pathogenic	no assertion criteria provided
2506442	NM_004483.5(GCSH):c.344C>T (p.Pro115Leu)	GCSH	Pathogenic	no assertion criteria provided
265683	NM_004483.5(GCSH):c.226C>T (p.Gln76Ter)	GCSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265685	NM_004483.5(GCSH):c.1A>G (p.Met1Val)	GCSH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081417	NM_004483.5(GCSH):c.317_318del (p.Val106fs)	GCSH	Likely pathogenic	criteria provided, single submitter
4819634	NM_004483.5(GCSH):c.380T>C (p.Leu127Pro)	GCSH	Likely pathogenic	criteria provided, single submitter
3893107	NM_004483.5(GCSH):c.515A>G (p.Glu172Gly)	GCSH	Uncertain significance	criteria provided, single submitter
4056491	NM_004483.5(GCSH):c.293-6A>C	GCSH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GCSH	Strong	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 7	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCSH	Orphanet:289857	Neonatal glycine encephalopathy
GCSH	Orphanet:289860	Infantile glycine encephalopathy
GCSH	Orphanet:289863	Atypical glycine encephalopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCSH	HGNC:4208	ENSG00000140905	P23434	Glycine cleavage system H protein, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCSH	Glycine cleavage system H protein, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCSH	Enzyme (other)	yes	1.4.1.27	Biotin_lipoyl, GCV_H, 2-oxoA_DH_lipoyl-BS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
amygdala	1
substantia nigra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCSH	134	ubiquitous	marker	C1 segment of cervical spinal cord, substantia nigra, amygdala

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCSH	2,079

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCSH	P23434	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycine degradation	1	1631.4×	1e-03	GCSH
Protein lipoylation	1	1038.2×	1e-03	GCSH

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine decarboxylation via glycine cleavage system	1	5617.3×	2e-04	GCSH

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCSH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCSH	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GCSH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GCSH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: GCSH