rs80338802

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM3PP3PP4PM2_SupportingPP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID:14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID:12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID:14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID:32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127306/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14O:1

Conservation

PhyloP100: 10.0

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant 4
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 9 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP1

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.2306G>A	p.Arg769Gln	missense_variant	Exon 22 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CAPN3	ENST00000397163.8 link	c.2306G>A	p.Arg769Gln	missense_variant	Exon 22 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1 link	c.311G>A	p.Arg104Gln	missense_variant	Exon 9 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1 link	c.311G>A	p.Arg104Gln	missense_variant	Exon 9 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1 link	c.311G>A	p.Arg104Gln	missense_variant	Exon 10 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1 link	c.311G>A	p.Arg104Gln	missense_variant	Exon 9 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 9 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1 link	n.*2742G>A		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1 link	n.*2742G>A		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251404

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000573

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:5Other:1

Jun 08, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM5,PP5(Moderate),PM2,PP3(Moderate),PP2,PM1,PS3(Supporting) -

Jul 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 06, 2025

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 glutamine, which is neutral and polar, at codon 769 of the CAPN3 protein (p.Arg769Gln). This variant is present in population databases (rs80338802, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 7762565, 7795603, 9246005, 12461690, 14645990). It is commonly reported in individuals of Amish ancestry (PMID: 9246005). ClinVar contains an entry for this variant (Variation ID: 17613). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 21, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:5

Dec 08, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP3, PM2, PM3, PS4 -

Sep 14, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30564623, 23553538, 9246005, 12461690, 16650086, 25252238, 28300015, 20301490, 19015733, 18258189, 14645990, 9642272, 7795603, 7762565, 31028937, 32668095, 31980526, 31589614, 35169782, 7720071) -

Mar 22, 2018

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:2

Apr 22, 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.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID: 14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID: 12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID: 32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence. -

Mar 19, 2025

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.2306G>A (p.Arg769Gln) results in a 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 allele was found at a frequency of 3.2e-05 in 251404 control chromosomes. c.2306G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1995, dePaula_2002). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.2305C>T, p.Arg769Trp), supporting the critical relevance of codon 769 to CAPN3 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7720071, 12461690). ClinVar contains an entry for this variant (Variation ID: 17613). Based on the evidence outlined above, the variant was classified as pathogenic. -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Mar 15, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Jun 05, 2024

Fulgent Genetics, Fulgent 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

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.090

T;.;.;D;.;.;.;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;.;D;.;D;.

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.42

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;.;.;M;.;.;.;.;.;.;.

PhyloP100

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

.;D;D;D;D;D;D;.;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;D;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;.;.;.;.;.;.;.

Vest4

0.98

MVP

0.99

MPC

0.68

ClinPred

1.0

GERP RS

5.4

Varity_R

0.93

gMVP

0.91

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over