ClinVar Genomic variation as it relates to human health

Variant summary: ACTN2 c.1426G>A (p.Ala476Thr) results in a non-conservative amino acid change located in one of the Spectrin repeats (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 277184 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0053 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 210 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 a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1426G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six 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 (VUS (2x), likely benign (3x), benign (1x)). Based on the evidence outlined above, the variant was classified as likely benign.

p.Ala476Thr in exon 13 of ACTN2: This variant is not expected to have clinical s ignificance because it has been identified in 0.53% (128/24020) of African chrom osomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs142943120).

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

ACTN2: BS1, BS2