Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000414202 | SCV000334022 | uncertain significance | not provided | 2018-05-17 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000414202 | SCV000491158 | likely pathogenic | not provided | 2023-03-01 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22926650, 26810512, 10330340, 30564623, 30919934, 32994280, 31555977, 35734998) |
Athena Diagnostics Inc | RCV000414202 | SCV000612634 | likely pathogenic | not provided | 2018-08-27 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. |
Invitae | RCV000644997 | SCV000766735 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 502 of the CAPN3 protein (p.Ile502Thr). This variant is present in population databases (rs148044781, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of autosomal recessive CAPN3-related conditions (PMID: 10330340, 26810512, 30919934; Invitae). ClinVar contains an entry for this variant (Variation ID: 282512). 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 80%. This variant disrupts the p.Ile502 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 18337726), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Counsyl | RCV000644997 | SCV000800676 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2018-03-20 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222470 | SCV002500731 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2023-12-13 | criteria provided, single submitter | clinical testing | Variant summary: CAPN3 c.1505T>C (p.Ile502Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250192 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00015 vs 0.0032), allowing no conclusion about variant significance. c.1505T>C has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Lahoria_2016, Ten Dam_2019, Barp_2020, Nallamilli_2018, Richard_1999, Becker_2022). These data indicate that the variant is 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: 31555977, 26810512, 30564623, 10330340, 30919934, 35135626). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Revvity Omics, |
RCV000414202 | SCV003830572 | likely pathogenic | not provided | 2023-08-09 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000414202 | SCV004136424 | likely pathogenic | not provided | 2023-08-01 | criteria provided, single submitter | clinical testing | CAPN3: PM1, PM5, PM2:Supporting, PP3 |
Baylor Genetics | RCV003475895 | SCV004211512 | likely pathogenic | Muscular dystrophy, limb-girdle, autosomal dominant 4 | 2023-10-24 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000644997 | SCV002085519 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2020-05-22 | no assertion criteria provided | clinical testing |