rs141656719
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PP4_ModeratePP3PM3
This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1468C>T variant in CAPN3 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 490 (p.Arg490Trp). This variant has been detected in at least 18 individuals with limb girdle muscular dystrophy (PMID:18055493, 10330340, 25214167, 25135358, 26632398, 12461690, 17994539), including in a homozygous state in at least two cases (1.0 pt; PMID:18055493), confirmed in trans with a pathogenic variant in one case (c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID:17994539), and in unknown phase with a pathogenic variant in four cases c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID:25135358; c.2279dup p.(Asn760LysfsTer5), 0.5 pts, PMID:18055493; c.2242C>T p.(Arg748Ter), 0.5 pts, PMID:25214167) (PM3_Very Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID:17994539). The highest population minor allele frequency of this variant is 0.0004598 (4/8700 genome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.84, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA233621/MONDO:0015152/187
Frequency
Genomes: đť‘“ 0.00013 ( 0 hom., cov: 32)
Exomes đť‘“: 0.00024 ( 0 hom. )
Consequence
CAPN3
NM_000070.3 missense
NM_000070.3 missense
Scores
13
2
4
Clinical Significance
Conservation
PhyloP100: -0.0230
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 5 ACMG points.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CAPN3 | NM_000070.3 | c.1468C>T | p.Arg490Trp | missense_variant | Exon 11 of 24 | ENST00000397163.8 | NP_000061.1 | |
| CAPN3 | NM_024344.2 | c.1468C>T | p.Arg490Trp | missense_variant | Exon 11 of 23 | NP_077320.1 | ||
| CAPN3 | NM_173087.2 | c.1324C>T | p.Arg442Trp | missense_variant | Exon 10 of 21 | NP_775110.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CAPN3 | ENST00000397163.8 | c.1468C>T | p.Arg490Trp | missense_variant | Exon 11 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
| ENSG00000258461 | ENST00000495723.1 | n.*1264C>T | non_coding_transcript_exon_variant | Exon 15 of 26 | 2 | ENSP00000492063.1 | ||||
| ENSG00000258461 | ENST00000495723.1 | n.*1264C>T | 3_prime_UTR_variant | Exon 15 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes 0.000132 AC: 20AN: 152084Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251162Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135758
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GnomAD4 exome AF: 0.000237 AC: 347AN: 1461786Hom.: 0 Cov.: 32 AF XY: 0.000260 AC XY: 189AN XY: 727200
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GnomAD4 genome 0.000131 AC: 20AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74408
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:8
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 08, 2014 | The p.Arg490Trp variant in CAPN3 has been reported in over 35 individuals with calpainopathy (LOVD Leiden Muscular Dystrophy database) in the homozygous and compound heterozygous state. Although this variant has been identified in 0.023% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141656719), its frequency is not high enough to rule out a pathogenic role. In summary, this variant meets our criteria to be classified as pathogenic based upon common observation in diseased individuals in the compound heterozygous state (http://pcpgm.partners.org/LMM). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Pathogenic, for Muscular dystrophy, limb-girdle, type 2A, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:17157502) (PMID:15221789). PS3 => Well-established functional studies show a deleterious effect (PMID:14578192,9642272). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 490 of the CAPN3 protein (p.Arg490Trp). This variant is present in population databases (rs141656719, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) 2A (PMID: 7720071, 14578192, 15221789, 16372320, 16971480, 17157502, 17994539, 18055493, 18563459, 18854869, 19015733, 21204801, 25135358, 25252031, 26632398, 27055500). ClinVar contains an entry for this variant (Variation ID: 166790). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 14578192, 16971480, 19226146). This variant disrupts the p.Arg409 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14578192, 15221789, 16971480, 17994539, 18563459, 21984748, 22378277). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2021 | Published functional studies demonstrate a damaging effect as R490W impairs the autocatalytic activity of the protein, slowing protein degradation as compared to controls (Fanin et al., 2003); 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: 20635405, 16971480, 15351423, 15221789, 12461690, 9150160, 31862442, 19226146, 17157502, 17994539, 16372320, 7720071, 21204801, 22995991, 9642272, 16627476, 26632398, 27500519, 30028523, 30919934, 18055493, 27535533, 14578192, 31589614, 25214167, 32528171) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 13, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 01, 2020 | The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | CAPN3: PM3:Strong, PM2, PM5, PP1, PP3 - |
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 09, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2024 | Variant summary: CAPN3 c.1468C>T (p.Arg490Trp) 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 8.4e-05 in 251162 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.1468C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (dePaula_2002, Fanin_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant affected the normal autocatalytic function (Fanin_2003). The following publications have been ascertained in the context of this evaluation (PMID: 14578192, 12461690). ClinVar contains an entry for this variant (Variation ID: 166790). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Jan 09, 2025 | The NM_000070.3: c.1468C>T variant in CAPN3 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 490 (p.Arg490Trp). This variant has been detected in at least 18 individuals with limb girdle muscular dystrophy (PMID: 18055493, 10330340, 25214167, 25135358, 26632398, 12461690, 17994539), including in a homozygous state in at least two cases (1.0 pt; PMID: 18055493), confirmed in trans with a pathogenic variant in one case (c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 17994539), and in unknown phase with a pathogenic variant in four cases c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 25135358; c.2279dup p.(Asn760LysfsTer5), 0.5 pts, PMID: 18055493; c.2242C>T p.(Arg748Ter), 0.5 pts, PMID: 25214167) (PM3_Very Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 17994539). The highest population minor allele frequency of this variant is 0.0004598 (4/8700 genome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.84, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4_Moderate, PP3. - |
CAPN3-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 20, 2023 | The CAPN3 c.1468C>T variant is predicted to result in the amino acid substitution p.Arg490Trp. This variant has been repeatedly reported in the compound heterozygous or homozygous state in individuals with limb-girdle muscular dystrophy (Gene referred to as CANP3 in Richard et al. 1995. PubMed ID: 7720071; Fanin et al. 2003. PubMed ID: 14578192; Krahn et al. 2011. PubMed ID: 21204801; Savarese et al. 2014. PubMed ID: 25214167; https://databases.lovd.nl/shared/genes/CAPN3). Functional studies indicate this variant disrupts the normal autocatalytic activity (Fanin et al. 2003. PubMed ID: 14578192). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42693952-C-T). This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.1468C>T;p.(Arg490Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 166790; PMID: 25135358; 26632398; 27055500; 30028523) - PS4.The variant is present at low allele frequencies population databases (rs141656719 – gnomAD 0.001315%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg490Trp) was detected in trans with a pathogenic variant (PMID: 25135358; 26632398; 27055500; 30028523) - PM3_strong. Pathogenic missense variant in this residue have been reported Clinvar ID: 17622) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 26632398) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
MVP
MPC
0.64
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at