15-42399601-G-A

Variant names:

• chr15-42399601-G-A
• rs149914792
• NM_000070.3:c.1303G>A

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Strong PP3 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1303G>A variant in CAPN3 is a missense variant expected to result in the substitution of glutamine for lysine at amino acid 435, p.(Glu435Lys). This variant has been detected in at least 8 individuals with features of LGMD (PMID:20635405, 35157181, 18854869, 38812636, 33931068, 30564623; LOVD CAPN3_000134), including in a homozygous state in two unrelated patients without reported familial consanguinity (0.5 pts x2 = 1.0 pt, PMID:35157181, 30564623, LOVD Individual #00222544). In addition, the variant was confirmed in trans with a likely pathogenic or pathogenic variant in at least three individuals (c.598_612del (p.Phe200_Leu204del), 1.0 pt, PMID:33931068; c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID:38812636; c.967G>T p.(Glu323Ter), 1.0 pt, PMID:18854869) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID:18854869) (PP4_Strong). The highest population minor allele frequency of this variant is 0.0003357 (15/44684 exome chromosomes) for the Admixed American population in gnomAD v4.1.0), which is higher than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.815, which is above the LGMD 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; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511313/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 8.06
• Publications: 5 publications found

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

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 7 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.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 23		NP_077320.1
CAPN3	NM_173087.2	c.1159G>A	p.Glu387Lys	missense_variant	Exon 9 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1303G>A	p.Glu435Lys	missense_variant	Exon 10 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1099G>A		non_coding_transcript_exon_variant	Exon 14 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1099G>A		3_prime_UTR_variant	Exon 14 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152172 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000839 AC: 21 AN: 250332 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000636 AC: 93 AN: 1461388 Hom.: 0 Cov.: 31 AF XY: 0.0000647 AC XY: 47 AN XY: 726958

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000336 AC: 15 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5608

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111866

Other (OTH) AF: 0.0000994 AC: 6 AN: 60362

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152290 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000815 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000218

EpiControl AF: 0.000298

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:5

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 20, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 435 of the CAPN3 protein (p.Glu435Lys). 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: 18854869, 20635405, 23553538, 33931068). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 282173). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic. -

Jan 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:5

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM1, PM3, PM2:Supporting, PP3 -

Aug 29, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state without a second identifiable CAPN3 variant in an individual with late onset limb girdle muscular dystrophy who had complete calpain-3 deficiency on Western blot (PMID: 15221789); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19226146, 16141003, 31589614, 32528171, 18854869, 11371436, 26363099, 34149409, Aksu2020[casereport], 20635405, 23553538, 35157181, 33931068, 38812636, 15221789) -

Nov 27, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Experiments performed in the paralagous protein, calpain-2 of rat, suggest this variant increases autocatalytic activity, however, it is unclear if this would also be true in calpain-3. 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. -

Apr 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

May 02, 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.1303G>A (p.Glu435Lys) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of 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 8.4e-05 in 250332 control chromosomes. 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.1303G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, hyperCkemia, or with clinical symptoms of a neuromuscular disorder or in heterozygous individuals without reported second variant (e.g. Ozyilmaz_2022, Fanin_2009, Saenz_2005, Piluso_2004, Topf_2020, Quick_2021). These data indicate that the variant is likely to be associated with disease. Several publications provide functional evidence suggesting the variant causes significant deficits of calpain-3 quantity and loss of autolytic activity in vitro (e.g. Fanin_2009) or accelerates autolytic degradation, lowering overall enzyme activity (e.g. Granham_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18854869, 19226146, 35157181, 16141003, 33931068, 15689361, 32528171). ClinVar contains an entry for this variant (Variation ID: 282173). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 14, 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.1303G>A variant in CAPN3 is a missense variant expected to result in the substitution of glutamine for lysine at amino acid 435, p.(Glu435Lys). This variant has been detected in at least 8 individuals with features of LGMD (PMID: 20635405, 35157181, 18854869, 38812636, 33931068, 30564623; LOVD CAPN3_000134), including in a homozygous state in two unrelated patients without reported familial consanguinity (0.5 pts x2 = 1.0 pt, PMID: 35157181, 30564623, LOVD Individual #00222544). In addition, the variant was confirmed in trans with a likely pathogenic or pathogenic variant in at least three individuals (c.598_612del (p.Phe200_Leu204del), 1.0 pt, PMID: 33931068; c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 38812636; c.967G>T p.(Glu323Ter), 1.0 pt, PMID: 18854869) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18854869) (PP4_Strong). The highest population minor allele frequency of this variant is 0.0003357 (15/44684 exome chromosomes) for the Admixed American population in gnomAD v4.1.0), which is higher than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.815, which is above the LGMD 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; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3. -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Likely 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

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy Pathogenic:1

Sep 02, 2021

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1303G>A;p.(Glu435Lys) variant has been published as a pathogenic variant in individuals affected with limb-girdle muscular dystrophy (PMID 15221789; 16141003; 18854869; 20635405; GeneOne, DASA) and ClinVar contains an entry for this variant (Variation ID: 13263) - PS4_moderate; variant is located in a mutational hot spot and/or critical and well-established functional domain (Calpain_III) - PM1; this variant is present in population databases (rs149914792 - gnomAD 0.0092% frequency; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting; variant detected in trans with a pathogenic variant (PMID 18854869; 20635405) - PM3_strong; this variant has been observed to segregate in a family (PMID: 20635405) - PP1; in silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.055	T;.;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.1	.;M;.;M
PhyloP100		8.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	.;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.021	.;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.99, 1.0, 0.99	.;D;D;D
Vest4		0.97
MVP		0.95
MPC		0.64
ClinPred		0.75	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.76
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs149914792; hg19: chr15-42691799;