GCSH

Chr 16AR

glycine cleavage system protein H

Also known as: GCE, MMDS7, NKH

NCBI Gene: 2653 ENSG00000140905 OMIM: 238330

The H protein encoded by GCSH shuttles the methylamine group of glycine from the P protein to the T protein in the mitochondrial glycine cleavage system and plays a pivotal role in the lipoylation of enzymes involved in cellular energetics. Mutations cause multiple mitochondrial dysfunctions syndrome 7 with autosomal recessive inheritance. This gene shows low constraint to loss-of-function variants, suggesting tolerance to complete protein loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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.[provided by RefSeq, Jan 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.421 OMIM phenotype

Clinical Summary— GCSH

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Gene-Disease Validity (ClinGen)

multiple mitochondrial dysfunctions syndrome 7 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 71 VUS of 153 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GCSH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.42LOEUF

pLI 0.002

Z-score 0.79

OE 0.68 (0.36–1.42)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.09Z-score

OE missense 0.97 (0.80–1.18)

70 obs / 72.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.36–1.42)

0≤0.351.4

Missense OE?0.97 (0.80–1.18)

0≤0.61.4

Synonymous OE?0.74

0≤1.21.6

LoF obs/exp: 5 / 7.3Missense obs/exp: 70 / 72.2Syn Z: 1.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGCSH-related glycine encephalopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6258th %ile

GOF

0.5170th %ile

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

153 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic7

VUS71

Likely Benign30

Benign30

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	3	0	7
Likely Pathogenic	5	2	0	0	7
VUS	0	68	2	1	71
Likely Benign	0	1	9	20	30
Benign	0	2	24	4	30
Conflicting	—				2
Total	7	75	38	25	147

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

42 pathogenic / likely-pathogenic (of 77) ClinVar copy-number / structural variants overlap GCSH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →