ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.956C>T (p.Pro319Leu)

gnomAD frequency: 0.00001  dbSNP: rs121434547
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000417420 SCV000338158 likely pathogenic not provided 2017-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000417420 SCV000515988 pathogenic not provided 2015-03-10 criteria provided, single submitter clinical testing The P319L variant in the CAPN3 gene has been reported previously in the compound heterozygous state inmultiple affected family members and one unrelated individual with limb-girdle muscular dystrophy type 2A(Richard et al., 1997; Piluso et al., 2005). The P319L variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however,data from ethnically-matched control individuals were not available to assess for a population-specific benignvariant. The P319L substitution is a semi-conservative amino acid substitution, which may impact secondaryprotein structure as these residues differ in some properties. This substitution occurs at a position that isconserved through mammals. In addition, missense variants in nearby residues (V320F, Y322H) have beenreported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson etal., 2014), supporting the functional importance of this region of the protein. We interpret P319L as a pathogenic variant.
Invitae RCV000019183 SCV000823087 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-12-29 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 319 of the CAPN3 protein (p.Pro319Leu). This variant is present in population databases (rs121434547, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 30056071, 30919934, 34602496). ClinVar contains an entry for this variant (Variation ID: 17617). 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) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000417420 SCV002025070 likely pathogenic not provided 2021-04-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473107 SCV004211542 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-10-07 criteria provided, single submitter clinical testing
OMIM RCV000019183 SCV000039471 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 1997-05-01 no assertion criteria provided literature only
Counsyl RCV000019183 SCV000795213 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2019-04-17 no assertion criteria provided clinical testing

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