ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.574G>A (p.Val192Ile)

gnomAD frequency: 0.00001  dbSNP: rs387906310
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586917 SCV000697172 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing Variant summary: The HEXA c.574G>A (p.Val192Ile) variant involves the alteration of a conserved nucleotide and is located in Glycoside hydrolase, catalytic domain (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be confirmed by functional studies. Another variant at the same residue, V192L, is an established pathogenic variant with concordant functional data (PMIDs: 8659543, 8198136, 2976595, and 1415222). Therefore the variant of interest may also be expected to impair the function of protein. This variant is absent in 121306 control chromosomes from ExAC. In literature, it has been reported in at least one brain autobiopsy sample without clear-cut information about clinical diagnosis (Clark _2015). Taken together, this variant is currently classified as Variant of Uncertain Significance.
Invitae RCV001834856 SCV002287534 uncertain significance Tay-Sachs disease 2022-10-28 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 192 of the HEXA protein (p.Val192Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 496013). 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. 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.
Natera, Inc. RCV001834856 SCV002086294 uncertain significance Tay-Sachs disease 2018-08-14 no assertion criteria provided clinical testing

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