Submissions for variant NM_000178.4(GSS):c.941C>T (p.Pro314Leu)

gnomAD frequency: 0.00292  dbSNP: rs75863437

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000009056	SCV000267351	uncertain significance	Inherited glutathione synthetase deficiency	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000601337	SCV000730286	benign	not specified	2017-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000009056	SCV001017324	benign	Inherited glutathione synthetase deficiency	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000009056	SCV001300623	benign	Inherited glutathione synthetase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000601337	SCV002500575	benign	not specified	2022-03-22	criteria provided, single submitter	clinical testing	Variant summary: GSS c.941C>T (p.Pro314Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251350 control chromosomes, including one homozygote in the general population (gnomAD). The variant occurs predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, which is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GSS causing Glutathione Synthetase Deficiency phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.941C>T has been reported in the literature in one individual affected with Glutathione Synthetase Deficiency (Shi_1996), occuring in cis with a second pathogenic variant (GSS c.1139_1144del, p.Val380_Gln381del), providing supporting evidence for a benign role. Experimental evidence evaluating protein function demonstrated the variant does not impact enzyme function in vitro (Njallson_2004) or in a yeast complementation assay (Shi_1996). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and three as benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002227019	SCV002506328	likely benign	not provided	2023-03-22	criteria provided, single submitter	clinical testing