Submissions for variant NM_033337.2(CAV3):c.216C>G (p.Cys72Trp)

gnomAD frequency: 0.00164  dbSNP: rs116840776

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171752	SCV000050766	likely benign	Limb-girdle muscular dystrophy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150236	SCV000197226	benign	not specified	2018-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga)	RCV000150236	SCV000227543	benign	not specified	2014-07-07	criteria provided, single submitter	clinical testing
Invitae	RCV001084478	SCV000261574	likely benign	Long QT syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000249612	SCV000317954	likely benign	Cardiovascular phenotype	2018-09-07	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000150236	SCV000740557	likely benign	not specified	2016-12-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000024381	SCV000885143	likely benign	not provided	2020-02-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769171	SCV000900546	likely benign	Cardiomyopathy	2019-11-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000769171	SCV000995703	likely benign	Cardiomyopathy	2019-03-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000987087	SCV001136285	benign	Long QT syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000024381	SCV001153761	benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CAV3: BS1, BS2
Illumina Laboratory Services, Illumina	RCV001144018	SCV001304592	uncertain significance	Caveolinopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150236	SCV001426790	likely benign	not specified	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: CAV3 c.216C>G (p.Cys72Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 283742 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 230 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAV3 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.216C>G has been reported in the literature in individuals with Muscular dystrophy, Long QT syndrome, Sudden Arrhythmic Death Syndrome, Dilated cardiomyopathy or Hypertrophic cardiomyopathy (McNally_1998, Arnestad_2007, Vatta_2006, Pugh_2014, Nunn_2015, Rubattu_2016, Sanchez_2016, Minoche_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. In addition, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1483C>T, p.Arg495Trp; TTN c.69491_69492del, p.Val23164fs) (Rubattu_2016, Minoche_2018), providing supporting evidence for a benign role. At least one publication reports this variant has no impact on protein function (Cai_2009). Ten ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (3x), likely benign (5x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics	RCV000150236	SCV001477112	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000024381	SCV001887388	benign	not provided	2018-11-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25630502, 31043699, 27600940, 25783436, 9536092, 23465283, 11251997)
PreventionGenetics, part of Exact Sciences	RCV003952349	SCV004766774	likely benign	CAV3-related disorder	2019-11-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Molecular Genetics, Royal Melbourne Hospital	RCV001144018	SCV004812488	likely benign	Caveolinopathy	2023-07-07	criteria provided, single submitter	clinical testing
OMIM	RCV000008769	SCV000028978	pathogenic	Rippling muscle disease 2	2005-01-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (CAV3)	RCV000024381	SCV000045674	not provided	not provided	2012-04-15	no assertion provided	curation
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477819	SCV000536872	uncertain significance	Elevated circulating creatine kinase concentration; Hypertrophic cardiomyopathy 1; Long QT syndrome 9; Rippling muscle disease 2; Distal myopathy, Tateyama type	2016-03-16	no assertion criteria provided	research