ClinVar

Description

Variant summary: TTR c.301G>A (p.Ala101Thr) results in a non-conservative amino acid change located in the transthyretin/hydroxyisourate hydrolase domain (IPR023416) of 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 1.2e-05 in 251436 control chromosomes (gnomAD). c.301G>A has been reported in the literature in multiple individuals affected with Transthyretin Amyloidosis, however often with limited evidence for causality (i.e. lack of segregation data or family history) (e.g. Benson_2003, Connors_2003, Obici_2012, Quarta_2014, Sperry_2018, Damy_2019). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further information becomes available.