ClinVar

Description

Variant summary: ACTN2 c.331G>A (p.Gly111Arg) results in a non-conservative amino acid change located in the Calponin homology domain (IPR001715) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251446 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.331G>A has been reported in the literature to not segregate with disease in a large family affected with dilated Cardiomyopathy in whom a causal variant in a different gene (TTN) was identified (Golbus_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.