Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000667520 | SCV000791988 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2017-06-02 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000667520 | SCV001217743 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 147 of the CAPN3 protein (p.Arg147Gln). This variant is present in population databases (rs139671324, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 17994539, 33337384). ClinVar contains an entry for this variant (Variation ID: 552291). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469243 | SCV002766582 | uncertain significance | not specified | 2022-11-15 | criteria provided, single submitter | clinical testing | Variant summary: CAPN3 c.440G>A (p.Arg147Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes (gnomAD). c.440G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Pathak_2021 and Guglieri_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |