Submissions for variant NM_033337.3(CAV3):c.125A>C (p.Glu42Ala)

gnomAD frequency: 0.00011  dbSNP: rs137901165

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472187	SCV000549188	uncertain significance	Long QT syndrome	2023-08-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 409255). This variant has not been reported in the literature in individuals affected with CAV3-related conditions. This variant is present in population databases (rs137901165, gnomAD 0.05%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 42 of the CAV3 protein (p.Glu42Ala).
Eurofins Ntd Llc (ga)	RCV000598341	SCV000705283	uncertain significance	not provided	2017-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255494	SCV001431921	uncertain significance	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: CAV3 c.125A>C (p.Glu42Ala) results in a non-conservative amino acid change located in the Caveolin, conserved site (IPR018361) of 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 2.8e-05 in 251224 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.125A>C in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000598341	SCV002525267	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV002411476	SCV002676163	uncertain significance	Cardiovascular phenotype	2023-04-13	criteria provided, single submitter	clinical testing	The p.E42A variant (also known as c.125A>C), located in coding exon 2 of the CAV3 gene, results from an A to C substitution at nucleotide position 125. The glutamic acid at codon 42 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002496771	SCV002781539	uncertain significance	Elevated circulating creatine kinase concentration; Hypertrophic cardiomyopathy 1; Long QT syndrome 9; Rippling muscle disease 2; Distal myopathy, Tateyama type	2021-10-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000598341	SCV004229523	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Computational tools predict that this variant is damaging.