Submissions for variant NM_033337.3(CAV3):c.244G>A (p.Val82Ile)

gnomAD frequency: 0.00005  dbSNP: rs112626848

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726760	SCV000329204	likely benign	not provided	2021-03-24	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24917393, 23631430, 31737537, 30847666)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457990	SCV000549195	uncertain significance	Long QT syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 82 of the CAV3 protein (p.Val82Ile). This variant is present in population databases (rs112626848, gnomAD 0.03%). This missense change has been observed in individual(s) with various cardiac conditions (PMID: 23631430, 24917393, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 279733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CAV3 function (PMID: 24917393). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	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	uncertain significance	Long QT syndrome 1	2022-06-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252075	SCV002523691	uncertain significance	See cases	2020-05-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PP2
Ambry Genetics	RCV002446508	SCV002732085	uncertain significance	Cardiovascular phenotype	2024-09-06	criteria provided, single submitter	clinical testing	The p.V82I variant (also known as c.244G>A), located in coding exon 2 of the CAV3 gene, results from a G to A substitution at nucleotide position 244. The valine at codon 82 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in association with long QT syndrome and sudden cardiac death (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This alteration was also noted to have a cell expression profile that was altered from the wildtype (Lariccia V et al. J. Biomed. Sci., 2014 Jun;21:58). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000726760	SCV003829253	uncertain significance	not provided	2023-05-17	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 (http://congresso.sifweb.org/archivio/cong35/congresso_abs_view.php?id=244). 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; http://exac.broadinstitute.org/), 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).