Submissions for variant NM_000178.4(GSS):c.4del (p.Ala2fs)

dbSNP: rs752560204

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345182	SCV000433621	uncertain significance	Inherited glutathione synthetase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	The GSS c.4delG (p.Ala2ProfsTer14) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Ala2ProfsTer14 variant has been reported in one study in which it was found in a compound heterozygous state with a missense variant in two siblings with glutathione synthetase (GS) deficiency. Control data are unavailable for this variant which is reported at a frequency of 0.0004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E. coli and yeast demonstrate that the variants result in 2% of expression levels and 10% GSS activity as compared to wildtype (Shi et al. 1996). Due to the potential impact of frameshift variants and supporting evidence, the p.Ala2ProfsTer14 variant is classified as a variant of unknown significance but suspicious for pathogenicity for glutathione synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000345182	SCV000695766	pathogenic	Inherited glutathione synthetase deficiency	2016-09-29	criteria provided, single submitter	clinical testing	Variant summary: The c.4delG (p.Ala2Profs) variant in GSS gene is a nonsense change that results in the loss of the 460 amino acids of GSS (~98%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The results of functional showed less than 10% GSS activity in pts fibroblasts as well as in bacterial expression system. . The variant is present in the large control population dataset of ExAC at a low frequency 0.0002 (25/120304 chrs tested), exclusively in individuals of European descent (0.00038; 15/66140).The latter frequency does not exceed the maximal expected frequency of a pathogenic allele (0.003) in this gene. The variant of interest has been reported in two brothers presented with oxoprolinuria, metabolic acidosis, haemolytic anemia and mental retardation. Taking together, the variant was classified as Pathogenic.
Revvity Omics, Revvity	RCV001782855	SCV002024924	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing
Invitae	RCV000345182	SCV004448841	pathogenic	Inherited glutathione synthetase deficiency	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala2Profs*14) in the GSS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GSS are known to be pathogenic (PMID: 12638941, 15717202). This variant is present in population databases (rs752560204, gnomAD 0.5%). This premature translational stop signal has been observed in individual(s) with gluthathione synthetase deficiency (PMID: 8896573). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 338302). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000345182	SCV000029269	pathogenic	Inherited glutathione synthetase deficiency	1996-11-01	no assertion criteria provided	literature only