ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.577G>A (p.Gly193Ser) (rs137852314)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657881 SCV000331249 pathogenic not provided 2016-06-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507435 SCV000603774 pathogenic not specified 2017-03-09 criteria provided, single submitter clinical testing
Invitae RCV000282708 SCV000768478 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 163 of the G6PD protein (p.Gly163Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs137852314, ExAC 0.04%). This variant is a common cause of glucose-6-phosphate dehydrogenase deficiency in South Asian populations (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). This variant is also known as G6PD Mahidol in the literature. ClinVar contains an entry for this variant (Variation ID: 10367). Experimental studies have shown that this missense change reduces protein stability and enzymatic activity (PMID: 8118045, 17959407, 22165289). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657881 SCV000779644 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The G163S variant in the G6PD gene, also known as G6PD Mahidol, has been reported previously in association with G6PD deficiency and is a common variant in the Asian population (Vulliamy et al., 1989; Sarker et al., 2016). Being a common variant, the G163S variant is observed in 7/19,142 alleles (0.037%) from individuals of South Asian background, including 3 unrelated hemizygous individuals, in the ExAC dataset (Lek et al., 2016). The G163S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In vitro studies showed that G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (Huang et al., 2008). We interpret G163S as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763205 SCV000893825 pathogenic Susceptibility to malaria; Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-10-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000282708 SCV001164403 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2018-12-03 criteria provided, single submitter research The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has been identified in 0.03657% (7/19142) of South Asian chromosomes, including 3 hemizygous individuals, and 0.01442% (2/13869) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852314). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, most individuals with non-spherocytic hemolytic anemia due to G6PD deficiency are asymptomatic. This variant has been reported pathogenic in ClinVar (Variation ID: 10367). The p.Gly193Ser variant in G6PD has been reported in 75 Southeast Asian individuals with G6PD Deficiency in the literature (PMID: 27880809, 2503817, 11499668, 15349799). The prevalence of this variant in affected individuals is significantly increased compared to the prevalence in large population studies, supporting pathogenicity. In vitro functional studies provide some evidence that the p.Gly193Ser variant may impact protein stability, activity, (PMID: 17959407, 8118045). In summary, the p.Gly193Ser variant is pathogenic. ACMG/AMP Criteria applied: PP3, PS3, PS4 (Richards 2015).
OMIM RCV000011085 SCV000031312 other G6PD MAHIDOL 2017-05-24 no assertion criteria provided literature only

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