Submissions for variant NM_000070.3(CAPN3):c.755T>C (p.Met252Thr)

gnomAD frequency: 0.00001  dbSNP: rs1555420652

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671167	SCV000796117	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671167	SCV000832587	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 252 of the CAPN3 protein (p.Met252Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive CAPN3-related conditions (PMID: 18854869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 16141003); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 555359). 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.Met252 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553721	SCV001774702	uncertain significance	not specified	2021-07-20	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.755T>C (p.Met252Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) 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 8e-06 in 251418 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.755T>C has been reported in the literature in at-least one comprehensively evaluated individual affected with Limb-Girdle Muscular Dystrophy (LGMD), Autosomal Recessive, who was compound heterozygous for this variant and c.1524+1G>C and whose muscle biopsy demonstrated 5% calpain quantity (Fanin_2009). This patient has been subsequently reported by others (example, Piluso_2005, Nascimbeni_2010). These data do not allow any conclusion about variant significance. 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 citing overlapping evidence utilized in the context of this evaluation. Of note, two other variants at the same codon, namely, p.M252R and p.M252K have also been reported in other patients with LGMD supporting the functional importance of this residue. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV003140069	SCV003822488	likely pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003140069	SCV005078088	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified with a second variant in an individual with limb girdle muscular dystrophy, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Fanin et al., 2009); Identified in an individual with limb girdle muscular dystrophy, but it is unknown whether this individual was tested for variants in other genes associated with muscular dystrophy (Piluso et al., 2005); This variant is associated with the following publications: (PMID: 18854869, 20635405, 16141003)