rs1555420652
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000070.3(CAPN3):āc.755T>Cā(p.Met252Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M252V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.755T>C | p.Met252Thr | missense_variant | 5/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.755T>C | p.Met252Thr | missense_variant | 5/23 | ||
CAPN3 | NM_173087.2 | c.755T>C | p.Met252Thr | missense_variant | 5/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.755T>C | p.Met252Thr | missense_variant | 5/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2023 | 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. - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2023 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 18, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at