Submissions for variant NM_000178.4(GSS):c.754C>T (p.Arg252Ter)

gnomAD frequency: 0.00001  dbSNP: rs749741013

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778631	SCV000914955	uncertain significance	Inherited glutathione synthetase deficiency	2018-10-15	criteria provided, single submitter	clinical testing	The GSS c.754C>T (p.Arg252Ter) variant is a stop-gained variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Arg252Ter variant is reported at a frequency of 0.000097 in the African population of the Exome Aggregation Consortium but this is based on one allele only in a region of good coverage so is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507984	SCV001713855	likely pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	PVS1, PM2
GeneDx	RCV001507984	SCV004014330	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000778631	SCV004673804	pathogenic	Inherited glutathione synthetase deficiency	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg252*) 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 (rs749741013, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with GSS-related conditions. ClinVar contains an entry for this variant (Variation ID: 631873). For these reasons, this variant has been classified as Pathogenic.