ClinVar

Description

Variant summary: SACS c.3427C>A (p.Gln1143Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251066 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0011 vs 0.0079), allowing no conclusion about variant significance. c.3427C>A has been reported in the literature in at-least one individual in a study of 171 individuals with ataxia of unknown etiology who underwent exome sequencing (example, Sun_2019). The reported individual did not present with Ataxia and had no supportive Brain MRI findings but had spastic paraplegia and lower extremity spasticity with no known family history. These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.