ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1292T>C (p.Val431Ala) (rs199625801)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486846 SCV000564828 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing The maternally inherited V431A variant in the CAPN3 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, a missense mutation at the same residue (V431M) has been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2009). The V431A variant was not observed at any significant frequency in approximately 6,500 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 V431A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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 (N434I, E435K) have been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2009), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we interpret V431A as a variant of uncertain significance.
Invitae RCV000644979 SCV000766709 uncertain significance Limb-girdle muscular dystrophy, type 2A 2017-12-08 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 431 of the CAPN3 protein (p.Val431Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs199625801, ExAC 0.01%). This variant has not been reported in the literature in individuals with CAPN3-related disease. ClinVar contains an entry for this variant (Variation ID: 418108). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Val431Met) has been reported in an individual affected with   limb-girdle muscular dystrophy (PMID: 10102422). However, the clinical significance of this variant is not known. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.