Submissions for variant NM_000520.6(HEXA):c.788C>T (p.Thr263Ile)

dbSNP: rs1057519462

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000416422	SCV001589167	pathogenic	Tay-Sachs disease	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 263 of the HEXA protein (p.Thr263Ile). 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: 23852624; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 375356). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000416422	SCV002073318	uncertain significance	Tay-Sachs disease		criteria provided, single submitter	clinical testing	The missense variant p.T263I in HEXA (NM_000520.6) has been submitted to ClinVar as Likely Pathogenic.However no clinical details are available to make an independent assesment. The p.T263I variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.T263I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 263 of HEXA is conserved in all mammalian species. The nucleotide c.788 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323529	SCV004028777	uncertain significance	not specified	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.788C>T (p.Thr263Ile) 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 was absent in 251470 control chromosomes (gnomAD). c.788C>T has been reported in the literature in individuals affected with Tay-Sachs Disease (example: sheth_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23852624). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000416422	SCV000494216	likely pathogenic	Tay-Sachs disease	2011-03-14	no assertion criteria provided	research