Submissions for variant NM_033337.3(CAV3):c.40G>A (p.Val14Ile)

gnomAD frequency: 0.00088  dbSNP: rs121909281

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150234	SCV000197220	likely benign	not specified	2014-05-15	criteria provided, single submitter	clinical testing	Val14Ile in exon 1 of CAV3: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (14/4406) of African American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs121909281). In addition, this variant is not conserved in mammals and of note, multiple mammals have an isoleucine (Ile) at this position despite hig h nearby amino acid conservation.
GeneDx	RCV000727218	SCV000207764	benign	not provided	2020-09-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25351510, 27312022, 26159999, 27066573)
Invitae	RCV001084128	SCV000560135	likely benign	Long QT syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727218	SCV000706713	uncertain significance	not provided	2017-03-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619202	SCV000737622	likely benign	Cardiovascular phenotype	2018-12-18	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770193	SCV000901621	likely benign	Cardiomyopathy	2020-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150234	SCV001362481	benign	not specified	2019-04-30	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000150234	SCV001880716	likely benign	not specified	2020-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727218	SCV004146816	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CAV3: BP4, BS1