ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.1478T>G (p.Val493Gly)

gnomAD frequency: 0.00003  dbSNP: rs794727049
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174253 SCV000225527 likely pathogenic not provided 2017-04-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001323093 SCV001513995 uncertain significance Sandhoff disease 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 493 of the HEXB protein (p.Val493Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HEXB-related conditions. ClinVar contains an entry for this variant (Variation ID: 193999). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004700533 SCV005204504 uncertain significance not specified 2024-06-11 criteria provided, single submitter clinical testing Variant summary: HEXB c.1478T>G (p.Val493Gly) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five 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 31406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1478T>G in individuals affected with Sandhoff Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 193999). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001323093 SCV002084948 uncertain significance Sandhoff disease 2021-10-07 no assertion criteria provided clinical testing

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