GCSH

Chr 16AR

glycine cleavage system protein H

Also known as: GCE, MMDS7, NKH

NCBI Gene: 2653ENSG00000140905UniProt: P23434

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]

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 7MIM #620423
AR
226
ClinVar variants
53
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GCSH
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 101 VUS of 226 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.09Z-score
OE missense 0.97 (0.80–1.18)
70 obs / 72.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.68 (0.36–1.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.80–1.18)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.74
0≤1.21.6
LoF obs/exp: 5 / 7.3Missense obs/exp: 70 / 72.2Syn Z: 1.04

ClinVar Variant Classifications

226 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic10
VUS101
Likely Benign31
Benign30
Conflicting2
43
Pathogenic
10
Likely Pathogenic
101
VUS
31
Likely Benign
30
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
2
39
0
43
Likely Pathogenic
3
1
6
0
10
VUS
0
68
32
1
101
Likely Benign
0
1
10
20
31
Benign
0
2
24
4
30
Conflicting
—2
Total57411125217

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

View in ClinVar →

Protein Context — Lollipop Plot

GCSH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GCSH-related glycine encephalopathy

strong
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Multiple mitochondrial dysfunctions syndrome 7

MIM #620423

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.
Arribas-Carreira L et al.·Hum Mol Genet
2023
Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia.
Abulimiti M et al.·Ann Hematol
2024
Comprehensive Analysis of the Relationship between Cuproptosis-Related Gene GCSH and Prognosis, Tumor Microenvironment Infiltration, and Therapy Response in Endometrial Cancer.
Zhao M et al.·Oncology
2024
Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.
Majethia P et al.·Clin Genet
2021Case report
Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.
Yuan HY et al.·Diabetes Obes Metab
2024
GCSH antisense regulation determines breast cancer cells' viability.
Adamus A et al.·Sci Rep
2018
GCSH promotes colorectal cancer progression by inhibiting Cuproptosis through the PI3K/AKT-FDX1 axis.
Guo X et al.·Funct Integr Genomics
2026
System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma.
Yan C et al.·J Transl Med
2022
Cuproptosis illustrates tumor micro-environment features and predicts prostate cancer therapeutic sensitivity and prognosis.
Cheng B et al.·Life Sci
2023
Mutation analysis of glycine decarboxylase, aminomethyltransferase and glycine cleavage system protein-H genes in 13 unrelated families with glycine encephalopathy.
Azize NA et al.·J Hum Genet
2014
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools