rs863224956
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000070.3(CAPN3):c.1343G>A(p.Arg448His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,449,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448C) has been classified as Pathogenic.
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.1343G>A | p.Arg448His | missense_variant | 10/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.1343G>A | p.Arg448His | missense_variant | 10/23 | ||
CAPN3 | NM_173087.2 | c.1199G>A | p.Arg400His | missense_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.1343G>A | p.Arg448His | missense_variant | 10/24 | 1 | NM_000070.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000128 AC: 3AN: 235170Hom.: 0 AF XY: 0.00000787 AC XY: 1AN XY: 127016
GnomAD4 exome AF: 0.00000759 AC: 11AN: 1449806Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8AN XY: 719596
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:6
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Arg448His variant in CAPN3 was identified by our study in three siblings with Limb-Girdle Muscular Dystrophy. This variant has been identified in 0.001303% (3/230304) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs863224956). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant impacts the same residue as the pathogenic p.Arg448Cys variant, supporting the possibility that a missense mutation at this position may not be tolerated (ClinVar Variation ID: 280038). This variant was reported in the compound heterozygous state in 3 individuals with Limb-Girdle Muscular Dystrophy, but no information on other variants in those individuals was available (PMID: 16141003, 10330340). Animal models in mice have shown that this variant causes Limb-Girdle Muscular Dystrophy with evidence of increased protein degredation and decreasing binding to titin (PMID: 21624972, 11371436). This variant has also been reported in ClinVar (Variation ID: 217149). In summary, this variant is pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PS3, PP1, PP3, PM3_Supporting (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.1343G>A(p.Arg448His) variant in CAPN3 gene has been reported in homozygous and compound heterozygous state in individuals affected with CAPN3 related disorder (Piluso G, et. al., 2005; Cerino M, et. al., 2020; Ganaraja VH, et. al., 2021). Experimental studies have shown that this missense change affects CAPN3 function (Ermolova N, et. al., 2011). This p.Arg448His variant is present with an allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic (multiple submissions). The amino acid change p.Arg448His in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 448 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breakthrough Genomics, Breakthrough Genomics | - | This variant was previously reported in individuals with autosomal recessive limb-girdle muscular dystrophy [PMID: 25135358, 20635405, 30919934]. Functional studies using animal models in mice have shown that this variant causes Limb-Girdle Muscular Dystrophy with evidence of increased protein degradation and decreasing binding to titin [PMID: 21624972, 11371436]. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 448 of the CAPN3 protein (p.Arg448His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 20635405, 25135358, 30919934; Invitae). ClinVar contains an entry for this variant (Variation ID: 217149). 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. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15138196, 21624972). This variant disrupts the p.Arg448 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7318636, 10330340, 16141003, 16650086, 18854869, 26404900, 27447704). 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:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2014 | - - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, flagged submission | clinical testing | Baylor Genetics | Oct 05, 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 | Sep 11, 2023 | Variant summary: CAPN3 c.1343G>A (p.Arg448His) 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 1.3e-05 in 235170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1343G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g., Fanin_2009, Stehlikova_2014, Ten Dam_2019). 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: 18854869, 25135358, 30919934). Five submitters have reported 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at