ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.814G>A (p.Gly272Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003502017 SCV004297645 likely pathogenic Tay-Sachs disease 2023-10-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 272 of the HEXA protein (p.Gly272Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Tay Sachs disease (PMID: 20363167). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HEXA protein function. Experimental studies have shown that this missense change does not substantially affect HEXA function (PMID: 20363167). Studies have shown that this missense change results in skipping of exon 8 and introduces a premature termination codon (PMID: 20363167). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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