GCSH

protein-coding

glycine cleavage system protein H

Gene summary

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]

MANE transcript

NM_004483.5

Inheritance

ClinVar variants

P:13U:72B:26

Top phenotype

Glycine encephalopathy

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr16:81,081,945-81,096,395

External References & Databases

Ensembl (ENSG00000140905)

Transcript & Mutation Effects

hg38 • Region Span ~14.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple mitochondrial dysfunctions syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957382

Submitter: PanelApp Australia

multiple mitochondrial dysfunctions syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957382

Submitter: G2P

multiple mitochondrial dysfunctions syndrome 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0957382

Submitter: ClinGen

*GCSH* was first reported in relation to autosomal recessive glycine encephalopathy in 2021 (Majethia, et al., 2021, PMID:33890291). Glycine encephalopathy is characterized by elevated levels of glycine in the cerebrospinal fluid and elevated glycine CSF/plasma ratios. Patients with classic glycine encephalopathy or nonketotic hyperglycinemia often present in the first few days of life with apneic epileptic encephalopathy, which progresses to coma and death or leads to absent psychomotor development, cortical blindness, intractable epilepsy, peripheral spasticity, and central hypotonia. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 7 variants (frameshift, nonsense, and missense) have been reported in 7 probands from 2 publications (PMID:33890291, PMID:36190515). Variants in this gene segregated with disease in 1 additional family member. The gene *GCSH* encodes the "H-protein" that is crucial to both mitochondrial one carbon metabolism, as well as essential bioenergetic enzymes. Specifically, the H protein is involved in the glycine cleavage system, which is the primary pathway for the catabolism of the amino acid glycine. Additionally, the H protein is involved in the lipoylation of pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. This gene-disease association is further supported by its biochemical function in the glycine cleavage system (PMID:36190515), bulk tissue expression (PMID:23715323), functional alteration in COS7 cells (PMID:36190515), and a knockout mouse model (PMID:33569080), for which homozygous knock outs are embryonic lethal by E10.5. The gene-disease relationship is also supported by interaction with the protein products of *AMT* and *GLDC* (PMID:15355973). Biallelic variants in *AMT* and *GLDC* have been well documented in association with glycine encephalopathy. In summary, there is definitive evidence to support the relationship between *GCSH* and autosomal recessive glycine encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the UNC Biocuration core on 04/12/2018. The original classification was disputed due to the absence of human genetic evidence at the time. A classification of strong was reached on 1/27/2022 by the Aminoacidopathy GCEP. A reevaluation on 12/17/2025 did not identify any new supportive or contradictory evidence, given the time since first publication in 2021 the classification was updated from Strong to Definitive.

infantile glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017354

Submitter: Orphanet

atypical glycine encephalopathySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0015010

Submitter: Orphanet

multiple mitochondrial dysfunctions syndrome 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957382

Submitter: Ambry Genetics

neonatal glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017353

Submitter: Orphanet

multiple mitochondrial dysfunctions syndrome 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957382

Submitter: Labcorp Genetics (formerly Invitae)

glycine encephalopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Glycine encephalopathyAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: There is no current effective treatment for severe disease, but children with variants associated with residual GCS enzyme activity treated aggressively early with sodium benzoate and N-methyl D-aspartate receptor site antagonists may have improved outcomes

Refs: 6790577; 12402263; 20301531; 21470805; 33890291; 36190515

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GCSH variants in ClinVar

6 Conditions Cataloged

Glycine encephalopathyTotal: 68

Inborn genetic diseasesTotal: 43

not providedTotal: 24

Multiple mitochondrial dysfunctions syndrome 7Total: 11

GCSH-related disorderTotal: 9

not specifiedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004483.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	20 clinvar	3 clinvar	24
missense	2 clinvar	1 clinvar	68 clinvar	2 clinvar	1 clinvar	74
nonsense		1 clinvar				1
start loss		2 clinvar	1 clinvar			3
frameshift	1 clinvar	4 clinvar				5
splice donor/acceptor (+/-2bp)		2 clinvar	2 clinvar			4
Total	3	10	72	22	4	111

Highest pathogenic variant AF is 0.000034882538

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004483.5	RefSeq	NP_004474.2	5	MANE Select
ENST00000315467.9	Ensembl	ENSP00000319531.3	5	MANE Select
ENST00000561801.2	Ensembl	ENSP00000457645.2	3	Standard
ENST00000564386.6	Ensembl	ENSP00000457630.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycine, serine and threonine metabolism - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
Ammonia Recycling
Glycine degradation
Metabolism of amino acids and derivatives

Biological Process

glycine catabolic process
protein lipoylation
glycine decarboxylation via glycine cleavage system
methylation

Molecular Function

aminomethyltransferase activity
protein binding

Cellular Component

mitochondrion
mitochondrial matrix
glycine cleavage complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315467
Coding exons: 5
Length: 14443
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125734
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0920	70	72.2	0.970	0.00000354	1068
Missense (PolyPhen)		12	20.284	0.59159		287
Synonymous	1.04	19	25.7	0.739	0.00000142	341
Loss of Function	0.791	5	7.31	0.684	3.07e-7	105

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000067	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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). {ECO:0000269|PubMed:1671321}.;
Disease: DISEASE: Non-ketotic hyperglycinemia (NKH) [MIM:605899]: Autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.164

Intolerance Scores

LoFtool: 0.708
RVIS EVS: 0.19
RVIS percentile EVS: 66.57

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.871

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium