ClinVar Miner

Submissions for variant NM_033337.3(CAV3):c.169G>A (p.Val57Met)

gnomAD frequency: 0.00001  dbSNP: rs116840795
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706810 SCV000835881 likely pathogenic Long QT syndrome 2023-03-09 criteria provided, single submitter clinical testing Studies have shown that this missense change alters CAV3 gene expression (PMID: 15099591). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 57 of the CAV3 protein (p.Val57Met). This variant is present in population databases (rs116840795, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant CAV3-related conditions (PMID: 15099591, 22581547, 26404900, 27772553; Invitae). ClinVar contains an entry for this variant (Variation ID: 31708). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171082 SCV001333752 uncertain significance Cardiomyopathy 2019-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000024391 SCV003798828 uncertain significance not provided 2023-01-31 criteria provided, single submitter clinical testing Identified in a patient with persistently elevated CK levels and reduced CAV3 in sarcolemma of muscle fibers on muscle biopsy; however, he was not otherwise symptomatic for muscular disorder, had a normal ECG, and his mother and brother who were also heterozygous for the variant had persistently elevated CK levels with no muscular symptoms (Alias et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15564037, 34426522, 27772553, 15099591, 22581547)
Revvity Omics, Revvity RCV000024391 SCV003829264 uncertain significance not provided 2022-06-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV004017265 SCV004848947 uncertain significance Cardiovascular phenotype 2018-12-20 criteria provided, single submitter clinical testing The c.169G>A (p.V57M) alteration is located in exon 2 (coding exon 2) of the CAV3 gene. This alteration results from a G to A substitution at nucleotide position 169, causing the valine (V) at amino acid position 57 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782023 SCV005394031 uncertain significance not specified 2024-09-04 criteria provided, single submitter clinical testing Variant summary: CAV3 c.169G>A (p.Val57Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251334 control chromosomes. c.169G>A has been reported in the literature in heterozygous individuals affected with Rippling Muscle Disease 2 (Alias_2004, Macias_2016, Magri_2015, Milone_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15099591, 27772553, 26404900, 22581547). ClinVar contains an entry for this variant (Variation ID: 31708). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Leiden Muscular Dystrophy (CAV3) RCV000024391 SCV000045685 not provided not provided 2012-04-15 no assertion provided curation

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