ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.721A>G (p.Ile241Val) (rs141948992)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726613 SCV000345827 uncertain significance not provided 2016-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000726613 SCV000619565 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing The c.721 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.721 A>G variant is observed in 19/66,740 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.721 A>G creates a cryptic splice donor site which may supplant the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change on splicing is unknown. If c.721 A>G does not alter splicing, it will result in the I241V missense change. The I241V 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 where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000806753 SCV000946769 uncertain significance Limb-girdle muscular dystrophy, type 2A 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 241 of the CAPN3 protein (p.Ile241Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs141948992, ExAC 0.03%). This variant has not been reported in the literature in individuals with CAPN3-related disease. ClinVar contains an entry for this variant (Variation ID: 291126). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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