ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.938C>T (p.Pro313Leu)

gnomAD frequency: 0.00003  dbSNP: rs752483058
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725159 SCV000334568 uncertain significance not provided 2015-08-25 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000302680 SCV000391006 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000358682 SCV000391007 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000725159 SCV000573687 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing The P313L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P313L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with CAPN3-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Athena Diagnostics Inc RCV000406817 SCV000612648 uncertain significance not specified 2017-04-12 criteria provided, single submitter clinical testing
Invitae RCV000358682 SCV000950591 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-10-07 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 313 of the CAPN3 protein (p.Pro313Leu). This variant is present in population databases (rs752483058, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 282867). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. 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.
Revvity Omics, Revvity RCV000725159 SCV003828928 uncertain significance not provided 2019-05-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000358682 SCV001454329 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-09-16 no assertion criteria provided clinical testing

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