ClinVar Miner

Submissions for variant NM_033337.3(CAV3):c.233C>T (p.Thr78Met) (rs72546668)

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Total submissions: 22
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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, Partners HealthCare 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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000039801 SCV000114283 likely benign not specified 2015-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000039801 SCV000167539 benign not specified 2012-04-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Blueprint Genetics RCV000039801 SCV000188740 benign not specified 2015-02-17 criteria provided, single submitter clinical testing
Invitae RCV000168328 SCV000219015 benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000242756 SCV000318969 likely benign Cardiovascular phenotype 2019-02-28 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000024406 SCV000602911 benign not provided 2018-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 Inc RCV000024406 SCV001143446 benign not provided 2019-06-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000024406 SCV001248495 likely benign not provided 2019-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
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.

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