ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.509G>A (p.Arg170Gln) (rs121907957)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000004106 SCV000792045 likely pathogenic Tay-Sachs disease 2017-06-08 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000004106 SCV000494209 pathogenic Tay-Sachs disease 2015-08-15 no assertion criteria provided research
GeneDx RCV000336253 SCV000329862 pathogenic not provided 2016-09-21 criteria provided, single submitter clinical testing The R170Q variant in the HEXA gene has previously been reported in association with Tay-Sachs disease (Nakano et al., 1990). Functional analysis of R170Q found that it is associated with significantly reduced enzyme activity and stability compared to wild-type (Nakano et al., 1990). The R170Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, another missense variant at the same position (R170W) has also been reported in the Human Gene Mutation Database in association with Tay-Sachs disease (Stenson et al., 2014). Therefore we interpret R170Q to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000004106 SCV000917509 pathogenic Tay-Sachs disease 2018-10-08 criteria provided, single submitter clinical testing Variant summary: HEXA c.509G>A (p.Arg170Gln) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 119570 control chromosomes. c.509G>A has been reported in the literature in individuals affected with Tay-Sachs Disease. In addition, a variant at the same codon has been associated with Tay-Sachs (p.R170W), suggesting the arginine is critical for protein function. Overall, these data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating enzyme activity in vitro, which showed the variant results in <10% of normal activity (Nakano_1990). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004106 SCV000024272 pathogenic Tay-Sachs disease 1990-05-01 no assertion criteria provided literature only

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