ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)

gnomAD frequency: 0.00001  dbSNP: rs121907983
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669552 SCV000794314 likely pathogenic Sandhoff disease 2017-09-22 criteria provided, single submitter clinical testing
Invitae RCV000669552 SCV001391079 pathogenic Sandhoff disease 2023-10-04 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 505 of the HEXB protein (p.Arg505Gln). This variant is present in population databases (rs121907983, gnomAD 0.01%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 8950198, 12027830, 23759947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3879). 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 HEXB protein function. Experimental studies have shown that this missense change affects HEXB function (PMID: 8357844). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000669552 SCV001442639 pathogenic Sandhoff disease 2020-10-18 criteria provided, single submitter clinical testing Variant summary: HEXB c.1514G>A (p.Arg505Gln) results in a conservative amino acid change located in the Glycoside hydroxylase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251186 control chromosomes. c.1514G>A has been reported in the literature in multiple individuals affected with adult and juvenile onset Sandhoff Disease (example, Redonnet-Vernhet_1996, Hara_1998, Sakuraba_2002, Utsumi_2002, Delnooz_2010, Clarke_2011, Gort_2012, Sobek_2012, Yasui_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe impairment of normal enzyme activity (example, Redonnet-Vernhet_1996). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000669552 SCV002024988 pathogenic Sandhoff disease 2021-08-26 criteria provided, single submitter clinical testing
OMIM RCV000004083 SCV000024249 pathogenic Sandhoff disease, adult form 1993-09-08 no assertion criteria provided literature only
Natera, Inc. RCV000669552 SCV002084952 pathogenic Sandhoff disease 2020-09-08 no assertion criteria provided clinical testing

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