ClinVar Miner

Submissions for variant NM_001234.5(CAV3):c.244G>A (p.Val82Ile) (rs112626848)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726760 SCV000329204 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing The V82I variant of uncertain significance in the CAV3 gene has been reported previously in a patient with LQTS who also harbored a variant in the KCNH2 gene (Lieve et al., 2013). This variant was also identified in a patient with suspected LQTS who experienced sudden cardiac death (SCD) (Lariccia et al., 2014). V82I has been observed in 11/33,556 (0.03%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The V82I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, biochemical and functional studies performed in heterologous cells demonstrated that the V82I variant results in increased protein stability but decreased cell surface expression; however, it is unclear how this altered expression profile would cause arrhythmia or cardiomyopathy (Lariccia et al., 2014).
Invitae RCV000457990 SCV000549195 uncertain significance Long QT syndrome 2020-08-01 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 82 of the CAV3 protein (p.Val82Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs112626848, ExAC 0.01%). This variant has been reported in individuals affected with long QT syndrome and sudden cardiac death (PMID: 23631430, 24917393). ClinVar contains an entry for this variant (Variation ID: 279733). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change causes increased protein expression, reduced targeting to the plasma membrane and impaired ERK activation (PMID: 24917393). In summary, this variant is a rare missense change that has shown to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726760 SCV000702867 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769174 SCV000900549 uncertain significance Cardiomyopathy 2016-03-22 criteria provided, single submitter clinical testing
Mendelics RCV000987089 SCV001136287 likely pathogenic Long QT syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000726760 SCV000925044 uncertain significance not provided 2016-12-16 no assertion criteria provided provider interpretation p.Val82Ile (c.244G>A) in exon 2 of the CAV3 gene (NM_033337.2) We have seen this variant in a person with HCM who also had a very likely pathogenic MYBPC3 variant. Testing was performed by Invitae. Given the lack of gene level evidence associating the CAV3 gene with hypertrophic cardiomyopathy and case data linking the variant to LongQT syndrome that is somewhat undercut by population frequency, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene level evidence for CAV3 Both knockout and transgenic mouse models of CAV3 show evidence of HCM with progressive diastolic dysfunction (Aravamudan et al, 2003; Ohsawa et al, 2004). Despite this, human data points towards CAV3 variants causing skeletal muscle disease, not cardiomyopathy. Hayashi et al (2004) reported two siblings with HCM and p.T63S in CAV3. The variant was not inherited from their mother, so it was assumed to have come from their affected father, who was unavailable for study. Variant level evidence for CAV3 Val82Ile The Val82Ile variant has been seen in at least 3 unrelated cases of Long QT syndrome (not including this patient's family). It has not been reported in association with cardiomyopathy. Lariccia et al., 2014 reported it in a person with adult-onset sudden cardiac death. Lieve et al., 2013 reported the variant in a person with Long QT who also had a varian in KCNH2. The Invitae report notes that, "The valine residue is moderately conserved and there is a small physicochemical difference between valine and Isoleucine. An abstract from the 35th congresso nazionale Della Soicieta Italiana di Farmacologia reported it in an Italian patient with Long QT ( Lariccia et al., 2014 reported that the variant caused increased protein expression, reduced targeting to the plasma membrane and impaired extracellular signal regulated kinase activation. The variant was reported online in 7 of 60,401 individuals (MAF: 0.0058%) in the Exome Aggregation Consortium Dataset (EXAC;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino descent. Specifically, the variant was observed in 3 of 33,239 individuals of non-Finnish European descent (0.005% MAF), 1 of 5,189 people of African descent (MAF: 0.0096%), 1 of 5752 people of Latino descent (MAF 0.0087%), 1 of 8,210 people of South Asian descent (MAF: 0.006%, and 1 of 449 people of Other descent (MAF: 0.001%) . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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