ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1505T>C (p.Ile502Thr)

gnomAD frequency: 0.00026  dbSNP: rs148044781
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000414202 SCV000334022 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing
GeneDx 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, LabCorp 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, Revvity RCV000414202 SCV003830572 likely pathogenic not provided 2023-08-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen 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, Inc. RCV000644997 SCV002085519 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-05-22 no assertion criteria provided clinical testing

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