GCSH

glycine cleavage system protein H

Basic information

Region (hg38): 16:81081945-81096395

Links

ENSG00000140905 ∙ NCBI:2653 ∙ OMIM:238330 ∙ HGNC:4208 ∙ Uniprot:P23434 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• glycine encephalopathy (Limited), mode of inheritance: AR
• neonatal glycine encephalopathy (Supportive), mode of inheritance: AR
• infantile glycine encephalopathy (Supportive), mode of inheritance: AR
• atypical glycine encephalopathy (Supportive), mode of inheritance: Unknown
• multiple mitochondrial dysfunctions syndrome 7 (Strong), mode of inheritance: AR
• glycine encephalopathy (Strong), mode of inheritance: AR
• multiple mitochondrial dysfunctions syndrome 7 (Moderate), mode of inheritance: AR
• multiple mitochondrial dysfunctions syndrome 7 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Glycine encephalopathy	AR	Biochemical	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	Biochemical; Neurologic; Ophthalmologic	6790577; 12402263; 20301531; 21470805; 33890291; 36190515

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GCSH gene.

• Glycine_encephalopathy (67 variants)
• Inborn_genetic_diseases (39 variants)
• not_provided (23 variants)
• GCSH-related_disorder (8 variants)
• Multiple_mitochondrial_dysfunctions_syndrome_7 (8 variants)
• not_specified (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GCSH gene is commonly pathogenic or not. These statistics are base on transcript: NM_000004483.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	18	3	22
missense	2		63	2	1	68
nonsense		1				1
start loss		1	1			2
frameshift	1	1				2
splice donor/acceptor (+/-2bp)		2				2
Total	3	5	65	20	4

Highest pathogenic variant AF is 0.0000348825

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GCSH	protein_coding	protein_coding	ENST00000315467	5	14443

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00160	0.709	125712	0	22	125734	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0920	70	72.2	0.970	0.00000354	1068
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000154	0.000149
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000797	0.0000791
Middle Eastern	0.000163	0.000163
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Metabolism;Glyoxylate metabolism and glycine degradation (Consensus)

Recessive Scores

• pRec: 0.164

Intolerance Scores

• loftool: 0.708
• rvis_EVS: 0.19
• rvis_percentile_EVS: 66.57

Haploinsufficiency Scores

• pHI: 0.749
• hipred: N
• hipred_score: 0.198
• ghis: 0.513

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.871

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gcsh

Gene ontology

• Biological process: glycine catabolic process;protein lipoylation;glycine decarboxylation via glycine cleavage system;methylation
• Cellular component: mitochondrion;mitochondrial matrix;glycine cleavage complex
• Molecular function: aminomethyltransferase activity;protein binding