ClinVar Genomic variation as it relates to human health

Variant summary: CALM3 c.165G>A alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251138 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.165G>A in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with another pathogenic variant has been observed in our laboratory (FLNC c.1880_1887delATGTGCGG, p.Asp672ValfsX16; internal testing), providing supporting evidence for a benign role. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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.