Submissions for variant NM_033337.3(CAV3):c.233C>T (p.Thr78Met)

gnomAD frequency: 0.00317  dbSNP: rs72546668

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000168328	SCV000050767	likely benign	Long QT syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039801	SCV000063490	likely benign	not specified	2015-08-12	criteria provided, single submitter	clinical testing	p.Thr78Met in exon 2 of CAV3: This variant has been reported in 1 individual wit h idiopathic hyper-CK-emia, 3 individuals with LQTS (one of whom had a second pa thogenic variant), 1 individual with DCM and limb-girdle muscular dystrophy (hom ozygous for this variant), and 1 infant with SIDS, and was not detected in >1500 control chromosomes (Reijneveld 2006, Vatta 2006, Cronk 2007, Traverso 2008). H owever, this variant is not expected to have clinical significance because it ha s been identified in 0.4% (276/66492) of European chromosomes and 0.46% (48/1037 6) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org/, dbSNP rs72546668).
Eurofins Ntd Llc (ga)	RCV000039801	SCV000114283	likely benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000024406	SCV000167539	benign	not provided	2020-07-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17275750, 24123366, 23640888, 18253147, 24070816, 24021552, 23465283, 22378279, 22245016, 22595201, 17060380, 26656175, 26159999, 27312022, 29367541, 28648120, 28898996, 30986657, 28988457, 31019283, 31043699)
Blueprint Genetics	RCV000039801	SCV000188740	benign	not specified	2015-02-17	criteria provided, single submitter	clinical testing
Invitae	RCV000168328	SCV000219015	benign	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242756	SCV000318969	likely benign	Cardiovascular phenotype	2019-02-28	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000024406	SCV000602911	benign	not provided	2019-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000024406	SCV000699769	benign	not provided	2016-08-22	criteria provided, single submitter	clinical testing	Variant Summary: CAV3 c.233C>T (p.T78M) affects a conserved nucleotide and 4/5 in-silico tools predict this variant to be damaging. The variant is located within the central hydrophobic transmembrane domain (amino acids 75106) of caveolin-3 and has previously been reported to be disease causing. In vitro functional studies have shown that T78M interacts with the cardiac sodium channel to promote increased persistent current. However, it may be meaningless to assess the effects that CAV3 mutations have on a single ion channel without being able to assess the effect on the action potential as a whole due to the complex regulatory nature of the different cardiac ion channels that localize within caveolae. Therefore, the finding that T78M CAV3 expressed heterologously in HEK293 cell lines stably expressing the most common (Q1077del) variant of SCN5A-encoded cardiac sodium channel can cause a five-fold increase in late sodium current should not be considered strong evidence for pathogenicity. Detection of CAV3 T78M in unrelated patients with various diseases has led to its repeated labeling as pathogenic in the literature. However, many of these patients had a co-occurrence that could explain most, if not all, of the presenting phenotype. Additionally, T78M was found in 379/124242 control chromosomes at a frequency of 0.0030505, which is more than 121 times the maximal expected frequency of a CAV3 pathogenic allele (0.000025), suggesting this variant is a benign polymorphism. Patient observations and limited in vitro characterization are not sufficient to conclude that CAV T78M is pathogenic. It is possible that CAV3 T78M may exert a pathogenic effect in association with other genetic factors, however in isolation, the evidence strongly supports a benign classification of this variant. Additionally, several reputable labs classify the variant as benign/likely benign. Taken together, this variant was classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000039801	SCV000740556	benign	not specified	2016-08-16	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000008790	SCV000883139	uncertain significance	Long QT syndrome 9	2018-11-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769173	SCV000900548	benign	Cardiomyopathy	2018-06-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000039801	SCV000930434	uncertain significance	not specified	2019-04-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000769173	SCV000995704	benign	Cardiomyopathy	2017-03-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000987088	SCV001136286	likely benign	Long QT syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000024406	SCV001143446	benign	not provided	2019-06-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000024406	SCV001248495	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	CAV3: BS1
Illumina Laboratory Services, Illumina	RCV001144019	SCV001304593	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.
Dept of Medical Biology, Uskudar University	RCV000168328	SCV004022049	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP2, PP3, BS1
PreventionGenetics, part of Exact Sciences	RCV003924817	SCV004746416	likely benign	CAV3-related disorder	2019-02-19	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).
OMIM	RCV000008790	SCV000029000	pathogenic	Long QT syndrome 9	2007-02-01	no assertion criteria provided	literature only
OMIM	RCV000008791	SCV000029001	pathogenic	Long QT syndrome 2/9, digenic	2007-02-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (CAV3)	RCV000024406	SCV000045700	not provided	not provided	2012-04-15	no assertion provided	curation
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000039801	SCV000280063	uncertain significance	not specified		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We have classified this variant as likely benign or perhaps conferring low and multifactorial risk (as opposed to causing Mendelian disease). This assessment is based on the presence of the variant in general population samples (reviewed below) and the fact that many of the cases of Mendelian disease with this variant also have a different pathogenic variant in another gene. The CAV3 variant has been reported in 3 unrelated individuals with long QT syndrome, 3 SIDS cases , 1 individual with dilated cardiomyopathy and 1 idiopathic hyper-CK-emia proband (Arnestad et al 2007; Cronk et al 2007; Vatta et al 2006). This is a non-conservative amino acid change with a polar Threonine replaced with a nonpolar Methionine. Threonine is highly conserved at position 78 and studies indicate that this region of the CAV3 gene (codons 74-100) codes for a functionally significant domain of the CAV3 protein (Traverso et al 2008). This domain seems to be involved in caveolae organelle formation in muscle cells however there is no data on function of this region in relation to cardiomyocites. Arnestad et al (2007) identified the variant in 1 out of 182 control individuals. Many of the individuals reported in the literature with this variant also had another variant that was deemed pathogenic. This would suggest that the variant as observed coincidentally. Based on these data, it is unlikely that this CAV3 variant causes Mendelian disease. It remains unknown whether it may contribute to cardiac risk in a more subtle fashion.