rs774685118

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 6 ACMG points: 6P and 0B. PP3PP4PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.398C>T variant in CAPN3 is a missense variant predicted to cause substitution of alanine by valine at position 133, p.(Ala133Val). This variant has been reported in two unrelated individuals with a clinical diagnosis of LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.598_612del p.(Phe200_Leu204del), 1.0 pt x2, PMID:16141003, LOVD individuals #00214184, #00214185; PM3_Strong, PP4). However, it has also been observed in a homozygous state or in trans with a second presumed diagnostic CAPN3 variant (c.133G>A p.(Ala45Thr), c.1303G>A (p.Glu435Lys)) in three individuals without a clear LGMD phenotype (ClinVar SCV001985435.3, SCV003509679.1 internal data communication). The filtering allele frequency of this variant is 0.0001855 (the upper threshold of the 95% CI of 16/86246 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Of note, the South Asian population also includes one homozygous individual of unknown age. The computational predictor REVEL gives a score of 0.959, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, while 6 Bayesian points were awarded to this variant based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (PM3_Strong, PP3, PP4), given the conflicting evidence, the VCEP has opted to classify it as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy (LGMD VCEP specifications version 1.0.0; 03/25/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511008/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:9

Conservation

PhyloP100: 7.91

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 Uncertain_significance. Variant got 6 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.398C>T	p.Ala133Val	missense_variant	Exon 3 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.398C>T	p.Ala133Val	missense_variant	Exon 3 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.398C>T	p.Ala133Val	missense_variant	Exon 3 of 21		NP_775110.1	P20807-2
LOC105370794	XR_932178.3 link	n.-154G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.398C>T	p.Ala133Val	missense_variant	Exon 3 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*194C>T		non_coding_transcript_exon_variant	Exon 7 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*194C>T		3_prime_UTR_variant	Exon 7 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251410

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461364

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000668

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Feb 07, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with limb-girdle muscular dystrophy who also harbored a second variant in CAPN3, however, it is unknown if these variants were on the same (in cis) or opposite (in trans) CAPN3 allele (PMID: 16141003); 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: 16141003) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM2, PM3:Supporting, PP3 -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:3

Jun 10, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 133 of the CAPN3 protein (p.Ala133Val). This variant is present in population databases (rs774685118, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 16141003). ClinVar contains an entry for this variant (Variation ID: 290335). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Oct 03, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN3 c.398C>T (p.Ala133Val) results in a non-conservative amino acid change located in the catalytic domain (IPR001300) 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 6e-05 in 251410 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no conclusion about variant significance. The variant, c.398C>T, has been reported in the literature in 2 individuals affected with Limb-Girdle Muscular Dystrophy, who were described as compound heterozygotes, however no 2nd variant was specified (Piluso_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy

Uncertain:1

Mar 25, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000070.3: c.398C>T variant in CAPN3 is a missense variant predicted to cause substitution of alanine by valine at position 133, p.(Ala133Val). This variant has been reported in two unrelated individuals with a clinical diagnosis of LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.598_612del p.(Phe200_Leu204del), 1.0 pt x2, PMID: 16141003, LOVD individuals #00214184, #00214185; PM3_Strong, PP4). However, it has also been observed in a homozygous state or in trans with a second presumed diagnostic CAPN3 variant (c.133G>A p.(Ala45Thr), c.1303G>A (p.Glu435Lys)) in three individuals without a clear LGMD phenotype (ClinVar SCV001985435.3, SCV003509679.1 internal data communication). The filtering allele frequency of this variant is 0.0001855 (the upper threshold of the 95% CI of 16/86246 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Of note, the South Asian population also includes one homozygous individual of unknown age. The computational predictor REVEL gives a score of 0.959, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, while 6 Bayesian points were awarded to this variant based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (PM3_Strong, PP3, PP4), given the conflicting evidence, the VCEP has opted to classify it as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy (LGMD VCEP specifications version 1.0.0; 03/25/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;.;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

.;H;H;H

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.76

MutPred

0.92

Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);

MVP

0.98

MPC

0.63

ClinPred

0.98

GERP RS

6.1

Varity_R

0.91

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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