ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121907957
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Counsyl RCV000004106 SCV000792045 likely pathogenic Tay-Sachs disease 2017-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV000004106 SCV001227309 pathogenic Tay-Sachs disease 2021-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 170 of the HEXA protein (p.Arg170Gln). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs121907957, gnomAD 0.0008%). This missense change has been observed in individuals with Tay-Sachs disease (PMID: 8490625, 16088929, 24518553). ClinVar contains an entry for this variant (Variation ID: 3900). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function. Experimental studies have shown that this missense change affects HEXA function (PMID: 2141777). Studies have shown that this missense change results in the activation of a cryptic splice site in exon 5 (PMID: 8490625). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004106 SCV000024272 pathogenic Tay-Sachs disease 1990-05-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004106 SCV000494209 pathogenic Tay-Sachs disease 2015-08-15 no assertion criteria provided research
GenomeConnect - GM1 RCV000004106 SCV001338919 not provided Tay-Sachs disease no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 04-04-2019 by Lab or GTR ID 506900. GenomeConnect-GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc. RCV000004106 SCV002089742 pathogenic Tay-Sachs disease 2017-03-17 no assertion criteria provided clinical testing

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