rs863224958
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong
The NM_000070.3(CAPN3):c.146G>A(p.Arg49His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,880 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R49C) 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.146G>A | p.Arg49His | missense_variant | 1/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.146G>A | p.Arg49His | missense_variant | 1/23 | ||
CAPN3 | NM_173087.2 | c.146G>A | p.Arg49His | missense_variant | 1/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.146G>A | p.Arg49His | missense_variant | 1/24 | 1 | NM_000070.3 | P2 | |
CAPN3 | ENST00000357568.8 | c.146G>A | p.Arg49His | missense_variant | 1/23 | 1 | |||
CAPN3 | ENST00000349748.8 | c.146G>A | p.Arg49His | missense_variant | 1/21 | 1 | |||
CAPN3 | ENST00000318023.11 | c.146G>A | p.Arg49His | missense_variant | 1/23 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727236
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 31, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 27, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 217151). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the CAPN3 protein (p.Arg49His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Oct 20, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Arg49His variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg49His variant in CAPN3 has been reported in the compound heterozygous state in 5 individuals with LGMD (PMID: 17318636, 16650086, 16100770, 16411092). The presence of this variant in combination with multiple CAPN3 variants (1 reported pathogenic, 2 reported VUS, and 2 loss of function variants not reported in ClinVar) and in 5 individuals with LGMD increases the likelihood that the p.Arg49His variant is pathogenic. Another missense variant at the same position, p.Arg49Cys, has been reported likely pathogenic in ClinVar (Variation ID: 193037). This raises the possibility that a change at this position would not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong, PM4_Supporting (Richards 2015). - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 13, 2023 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: CAPN3 c.146G>A (p.Arg49His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes (gnomAD). c.146G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Krahn_2007, Monies-2016, Saat_2021, and Ozyilmaz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35157181, 27671536, 33963534, 16650086). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 04, 2020 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at