ClinVar Miner

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

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Total submissions: 4
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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."
Invitae RCV000009051 SCV001206943 pathogenic Gluthathione synthetase deficiency 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 164 of the GSS protein (p.Arg164Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 5 of the GSS coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121909307, ExAC 0.003%). This variant has been observed in individuals with gluthathione synthetase deficiency (PMID: 25851806,15717202, 28822442, 8896573). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8525). This variant has been reported to affect GSS protein function (PMID: 8896573). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant 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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