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Intellectual disability
Gene: GCSH

GCSH (glycine cleavage system protein H)
EnsemblGeneIds (GRCh38): ENSG00000140905
EnsemblGeneIds (GRCh37): ENSG00000140905
OMIM: 238330, Gene2Phenotype
GCSH is in 5 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.

Panel Version: 5.286

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 11 Oct 2023, 9:34 a.m.
Last Modified: 11 Oct 2023, 9:34 a.m.
Panel version: 5.286

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: This gene has sufficient evidence (four unrelated cases) to be promoted to GREEN at the next NHS GMS review.
Created: 13 Mar 2023, 10:42 p.m. | Last Modified: 13 Mar 2023, 10:42 p.m.

Panel Version: 4.117

PMID:36190515 reported six unrelated individuals with biallelic variants in GCSH. They presented with a broad clinical spectrum with three cases with an early-onset severe fatal glycine encephalopathy and the other three cases displaying an attenuated phenotype of developmental delay, behavioural problems, epilepsy and variable movement problems and they had long-term survival. The three early-onset and fatal cases displayed compound heterozygous variants, while the cases with attenuated phenotype harboured homozygous variants.

The cases with the early-onset severe fatal glycine encephalopathy did not survive to develop intellectual disability/ developmental delay. The three patients with the attenuated phenotype had global developmental delay and limited communication skills while two of these cases had behavioural problems as well.

Functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies demonstrated that most variants identified in this cohort produced a hypomorphic effect on both protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affected primarily one function only.

This gene has also been associated with Glycine encephalopathy in both OMIM and Gene2Phenotype.
Created: 13 Mar 2023, 10:35 p.m. | Last Modified: 13 Mar 2023, 10:35 p.m.

Panel Version: 4.114

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Glycine encephalopathy, OMIM:605899; Neurodevelopmental disorder, MONDO:0700092

Publications

36190515

Created: 13 Mar 2023, 10:35 p.m.
Last Modified: 13 Mar 2023, 10:35 p.m.
Panel version: 4.114

Sarah Leigh (Genomics England Curator)

Comment on publications: PMID 25231368 & 29304759 report no GCSH variants in Glycine encephalopathy 605899
Created: 5 Mar 2018, 12:27 p.m.

Associated with phenotype in OMIM and as a possible G2P association. At least 1 variant reported in 1 case.
Reported to be linked to isolated ID and ID associated disorders (PMID 26503795) and as candidate ID gene (PMID 24896178)
Created: 5 Mar 2018, 12:12 p.m.

Created: 5 Mar 2018, 12:12 p.m.

Panel version: Imported from Intellectual disability update Jan 2018 panel version 0.304

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
GLYCINE ENCEPHALOPATHY

Publications

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:03 a.m.

Panel version: 0.306

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
NHS GMS
Radboud University Medical Center, Nijmegen

Phenotypes

Multiple mitochondrial dysfunctions syndrome 7, OMIM:620423
Glycine encephalopathy
Transient neonatal hyperglycinemia

OMIM

238330

Clinvar variants

Variants in GCSH

Penetrance

Complete

Publications

36190515

Panels with this gene

History Filter Activity

11 Oct 2023, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: GCSH were changed from ?Glycine encephalopathy, OMIM:605899; Neurodevelopmental disorder, MONDO:0700092 to Multiple mitochondrial dysfunctions syndrome 7, OMIM:620423; Glycine encephalopathy; Transient neonatal hyperglycinemia

11 Oct 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q1_23_promote_green was removed from gene: GCSH.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to GCSH. Source Expert Review Green was added to GCSH. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

13 Mar 2023, Gel status: 2