Submissions for variant NM_033337.3(CAV3):c.442C>T (p.Arg148Trp)

gnomAD frequency: 0.00002  dbSNP: rs730880422

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157841	SCV000207771	likely pathogenic	not provided	2014-06-25	criteria provided, single submitter	clinical testing	This variant is denoted p.Arg148Trp (CGG>TGG): c.442 C>T in exon 2 of the CAV3 gene (NM_033337.2). The R148W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R148W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R148W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (S141R) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in ARRHYTHMIA panel(s).
Illumina Laboratory Services, Illumina	RCV001144022	SCV001304596	uncertain significance	Caveolinopathy	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171083	SCV001333753	uncertain significance	Cardiomyopathy	2019-02-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223776	SCV001448574	uncertain significance	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: CAV3 c.442C>T (p.Arg148Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442C>T has been reported in the literature in at least one individual affected with atrial fibrillation (e.g. Goodyer_2019). This report does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850194	SCV002179323	uncertain significance	Long QT syndrome	2024-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 148 of the CAV3 protein (p.Arg148Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with atrial fibrillation (PMID: 31638414). ClinVar contains an entry for this variant (Variation ID: 180801). 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 disruptive. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000157841	SCV002542025	uncertain significance	not provided	2021-06-02	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223776	SCV000280064	uncertain significance	not specified	2012-03-28	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. Given that there is no data associating wither this gene or this variant with atrial fibrillation we consider this variant a variant of uncertain significance. The variant is novel. We could find no reports of it either with disease or in the general population. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging with a score of 0.967. The arginine at codon 148 is highly, but not completely conserved across species. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 23rd, 2014). However, a different missense variant at the same codon, p.Arg148Gln, was observed in 2 of 2203 African Americans (and 0 of 4300 European Americans) The only variation at this codon listed in dbSNP is that variant from ESP (as of July 23rd, 2014).