ClinVar

Description

Variant summary: HEXA c.1435G>A (p.Ala479Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain 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 0.00082 in 277154 control chromosomes, predominantly at a frequency of 0.0084 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1435G>A has been reported in the literature, without strong evidence for causality (Strom_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified variant as VUS (n=1), likely benign (n=3), and benign (n=4). One of these labs also published an abstract in which they tested 4-5 patient samples for the variant of interest and found HexA enzyme analysis to show negative Tay-Sachs carrier state for all subjects (Counsyl abstract from Molecular Genetics and Metabolism, 2018). Based on the evidence outlined above, the variant was classified as benign.