ClinVar

Description

Variant summary: HEXA c.8G>C (p.Ser3Thr) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250174 control chromosomes and was also observed predominantly in the Ashkenazi Jewish subpopulation at a frequency of 0.0056 (56/10048). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975), suggesting this is likely a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.8G>C has been reported in the literature in individuals not affected with Tay-Sachs Disease. These reports do not provide unequivocal conclusions about association of the variant with Tay-Sachs Disease. Two publications showed that inviduals carrying this variant have normal HEXA activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.