ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.334C>T (p.Arg112Cys) (rs104894834)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000482440 SCV000110115 pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing
GeneDx RCV000482440 SCV000568187 pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing The R112C missense variant in the GLA gene has been reported previously in association with Fabrydisease (Yasuda et al., 2003; Lukas et al., 2013). Functional analyses of R112C are associated withsignificantly reduced enzyme activity compared to wild type (Ishii et al., 1992; Yasuda et al., 2003;Lukas et al., 2013). This variant was not observed in approximately 6500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. R112C is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/orother properties. It occurs at a position that is conserved across species, and in silico analysis predictsthis variant is probably damaging to the protein structure/function. Missense variants in the sameresidue (R112S; R112H) have been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson et al., 2014), supporting the functional importance of this region of theprotein. In summary, we interpret R112C to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780291 SCV000917444 pathogenic Fabry disease 2018-05-25 criteria provided, single submitter clinical testing Variant summary: GLA c.334C>T (p.Arg112Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 87742 control chromosomes (in ExAC). c.334C>T has been reported in the literature in multiple individuals affected with Fabry Disease, with (hemizygous) males being more severely affected than heterozygous women (e.g. Wilcox 2012, Shin 2008, Pieroni 2003). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function (Shin 2008, Pieroni 2003). The most pronounced variant effect results in <10% of normal activity in male patients (hemizygotes). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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