Description
Variant summary: CAV3 c.40G>A (p.Val14Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251318 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAV3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.40G>A, has been reported in the literature in individuals with exercise intolerance and rhabdomyolysis, LQTS, HCM or dysferlinopathy (Scalco_2016, Ghouse_2015, Lopes_2015, Izumi_2015). The patient diagnosed with dyserflinopathy also carried another likely pathogenic DYSF variant, c.1667C>T (p.L556P)(Izumi_2005). One publication, Scalco_2016, reports that immunohistochemistry indicated Caveolin-3 was normal but western blot showed expression level of Caeolin-3 was decreased. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant three times as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
