Submissions for variant NM_000520.6(HEXA):c.964G>T (p.Asp322Tyr)

dbSNP: rs772180415

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000207019	SCV000262575	pathogenic	Tay-Sachs disease	2011-10-02	criteria provided, single submitter	clinical testing	This variant found to be pathogenic by online software including Mutation Taster, Polyphen2 and SIFT.
Counsyl	RCV000207019	SCV000487232	likely pathogenic	Tay-Sachs disease	2016-11-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000207019	SCV001400896	pathogenic	Tay-Sachs disease	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 322 of the HEXA protein (p.Asp322Tyr). This variant is present in population databases (rs772180415, gnomAD 0.006%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 22390110, 22723944, 23852624). ClinVar contains an entry for this variant (Variation ID: 221281). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000207019	SCV002023462	likely pathogenic	Tay-Sachs disease	2019-06-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000207019	SCV004037621	pathogenic	Tay-Sachs disease	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.964G>T (p.Asp322Tyr) 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 8e-06 in 251390 control chromosomes (gnomAD). c.964G>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Tay-Sachs Disease, gangliosidosis and suspected neurological disorders (Chan_2011, Sheth_2013, Ganapathy_2019, Mistri_2019, Gowda_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22390110, 31069529, 35186388, 31388111, 22723944, 23852624). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000207019	SCV004100652	pathogenic	Tay-Sachs disease		criteria provided, single submitter	clinical testing	The missense variant p.D322Y in HEXA (NM_000520.6) has been reported previously in multiple affected individuals of Indian origin(Sheth J et al, Mistri M et al). The variant has been submitted to ClinVar as Likely Pathogenic/Pathogenic. The p.D322Y variant is observed in 2/30,616 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.D322Y missense variant is predicted to be damaging by both SIFT and PolyPhen2. The aspartic acid residue at codon 322 of HEXA is conserved in all mammalian species. The nucleotide c.964 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.