rs141656719

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PP4_ModeratePM3PP3

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: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:23

Conservation

PhyloP100: -0.0230

Variant links:

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]

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

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 link	c.1468C>T	p.Arg490Trp	missense_variant	Exon 11 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.1468C>T	p.Arg490Trp	missense_variant	Exon 11 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.1324C>T	p.Arg442Trp	missense_variant	Exon 10 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.1468C>T	p.Arg490Trp	missense_variant	Exon 11 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*1264C>T		non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*1264C>T		3_prime_UTR_variant	Exon 15 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251162

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

347

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

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

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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. -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:8

Jun 24, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM3:Strong, PM2, PM5, PP1, PP3 -

Sep 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 08, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:2

Feb 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Jan 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

CAPN3-related disorder

Pathogenic:2

Feb 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;D

Eigen

Benign

-0.066

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.5

.;H;.;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.8

.;D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.93

MVP

0.92

MPC

0.64

ClinPred

0.92

GERP RS

-3.7

Varity_R

0.87

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over