ClinVar Miner

Submissions for variant NM_000178.4(GSS):c.491G>A (p.Arg164Gln) (rs121909307)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000009051 SCV000433620 pathogenic Gluthathione synthetase deficiency 2017-04-28 criteria provided, single submitter clinical testing The GSS c.491G>A (p.Arg164Gln) variant has been reported in three studies in individuals with 5-oxoprolinuria (a marker for glutathione synthetase deficiency), including two in a homozygous state, three in a compound heterozygous state with either another missense variant or a deletion variant, and in one heterozygote in whom the second variant was not identified (Shi et al. 1996; Tokatli et al. 2007; Li et al. 2015). The c.491G>A (p.Arg164Gln) variant was absent from 25 controls and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on two alleles only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies in individual fibroblasts and erythrocytes demonstrated that the variant resulted in a defect in splicing and enzyme activity of only 5% of normal levels. Expression of p.Arg164Gln variant cDNAs in both yeast and E. coli showed no detectable GSS activity and a failure to complement growth in yeast (Shi et al. 1996; Tokatli et al. 2007). Based on the collective evidence, the p.Arg164Gln variant is classified as pathogenic for glutathione synthetase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000009051 SCV000695765 pathogenic Gluthathione synthetase deficiency 2016-11-23 criteria provided, single submitter clinical testing Variant summary: The GSS c.491G>A (p.Arg164Gln) variant causes a missense change involvign a conserved nucleotide, however, the variant is located at the last 3' position of the exon (Shi_1996), a known location to affect splicing, which 5/5 splice prediction tools predict an affect on splicing that is supported by a functional study, Shi_1996. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/117694 (1/58847), which does not exceed the estimated maximal expected allele frequency for a pathogenic GSS variant of 1/338. The variant of interest was observed in multiple affected individuals via publications in a homozygous or compound heterozygous state. GSS activity in these patients were significantly decreased (Shi_1996 and Njalsson_2005). In addition, a reputable database, OMIM, cites the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
OMIM RCV000009051 SCV000029268 pathogenic Gluthathione synthetase deficiency 1996-11-01 no assertion criteria provided literature only

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