ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.133G>A (p.Ala45Thr)

gnomAD frequency: 0.00001  dbSNP: rs774048743
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000201177 SCV000255650 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2014-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000201177 SCV000793199 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-08-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000762947 SCV000893371 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000201177 SCV001224973 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 45 of the CAPN3 protein (p.Ala45Thr). This variant is present in population databases (rs774048743, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15351423, 16650086, 18055493, 19556129). ClinVar contains an entry for this variant (Variation ID: 217148). 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%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001781585 SCV002016922 pathogenic not provided 2020-03-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235123 SCV003934028 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2023-05-08 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.133G>A (p.Ala45Thr) results in a non-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 251398 control chromosomes (gnomAD). c.133G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Chrobakova_2004, Groen_2007). These data indicate that the variant is very likely to 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: 15351423, 18055493). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001781585 SCV005201648 likely pathogenic not provided 2023-12-12 criteria provided, single submitter clinical testing Published functional studies demonstrate no detectable protein in the muscle tissue of a patient homozygous for this variant (PMID: 15351423); Identified in patients with limb-girdle muscular dystrophy who also harbored a second variant in CAPN3, however, it is unknown if these variants were on the same (in cis) or opposite (in trans) CAPN3 allele (PMID: 16650086, 19556129); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19556129, 16372320, 16650086, 17157502, 18055493, 37526466, 15351423)
GeneReviews RCV000201177 SCV002015207 not provided Autosomal recessive limb-girdle muscular dystrophy type 2A no assertion provided literature only
Baylor Genetics RCV003462346 SCV004213775 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-05-03 flagged submission clinical testing

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