Evidence Repository - Clinical Genome Resources

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Variant: NM_000070.3(CAPN3):c.1322G>A (p.Gly441Asp)

CA391999585

2137655 (ClinVar)

Gene: CAPN3 (HGNC:825)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: 6ed54c3c-fa04-46be-9621-51dad94be0d1

Approved on: 2025-10-29

Published on: 2025-11-11

HGVS expressions

NM_000070.3(CAPN3):c.1322G>A (p.Gly441Asp)

NM_000070.3:c.1322G>A

NC_000015.10:g.42399620G>A

CM000677.2:g.42399620G>A

NC_000015.9:g.42691818G>A

CM000677.1:g.42691818G>A

NC_000015.8:g.40479110G>A

NG_008660.1:g.56518G>A

ENST00000349748.8:c.1178G>A

ENST00000357568.8:c.1322G>A

ENST00000397163.8:c.1322G>A

ENST00000466369.5:n.1831G>A

ENST00000483208.5:n.1553G>A

ENST00000495723.1:n.1553G>A

ENST00000549793.5:n.1553G>A

ENST00000638141.2:n.1193G>A

ENST00000673658.1:n.306G>A

ENST00000673705.1:c.277G>A

ENST00000318023.11:c.1178G>A

ENST00000349748.7:c.1178G>A

ENST00000357568.7:c.1322G>A

ENST00000397163.7:c.1322G>A

NM_000070.2:c.1322G>A

NM_024344.1:c.1322G>A

NM_173087.1:c.1178G>A

NM_024344.2:c.1322G>A

NM_173087.2:c.1178G>A

Likely Pathogenic

PP3 PM3 PP4_Strong PM2_Supporting

PP1 PM5

Evidence Links 0

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000070.3: c.1322G>A variant in CAPN3 is a missense variant expected to result in the substitution of glycine with aspartic acid at amino acid 441, p.(Gly441Asp). This variant has been reported in four individuals with features consistent with LGMD (PMID: 16372320, 37526466, 16650086, 25135358; ClinVar SCV003442816.3 internal data communication), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts; PMID: 16372320, 37526466, 25135358) and in unconfirmed phase with a pathogenic variant in two patients (c.550del p.(Thr184ArgfsTer36), 0.5 pts, ClinVar SCV003442816.3 internal data communication; c.1714C>T p.(Arg572Trp), 0.5 pts, PMID: 16650086) (PM3). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and only trace amounts of calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 16650086). The variant is not found in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely 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 2.0.0; 10/29/2025): PM3, PP4_Strong, PM2_Supporting, PP3.

PP3

The computational predictor REVEL gives a score of 0.916, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). SpliceAI 0.01, not in a splice region

PM3

This variant has been reported in four individuals with features consistent with LGMD (PMID: 16372320, 37526466, 16650086, 25135358; ClinVar SCV003442816.3 internal data communication), including in a homozygous state without reported familial consanguinity in one patient (0.5 pts; PMID: 16372320, 37526466, 25135358) and in unconfirmed phase with a pathogenic variant in two patients (c.550del p.(Thr184ArgfsTer36), 0.5 pts, ClinVar SCV003442816.3 internal data communication; c.1714C>T p.(Arg572Trp), 0.5 pts, PMID: 16650086) (PM3). cannot asses co-occurrence predictions with variants in unconfirmed phase no other patients identified: In LOVD, Saenz et al. (2005) and Richard et al. (1999) each report a single hit. No other cases in LOVD. Fardeau et al. (1996) (PMID: 9027854) don't provide individual details and is a French study with potential overlap with Richard et al. and Krahn et al. Jia et al. (2003) (PMID: 11371436) is a modeling study that doesn't report any patients.

PP4_Strong

At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and only trace amounts of calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 16650086). 35 year old female with LGMD symptoms since childhood. Western blot of muscle biopsy: 30 kDa 0 (absent), 60 kDa 0/— (trace), 94 kDa 0/— (trace). Unconfirmed phase with c.1714C>T (p.Arg572Trp), which is provisionally P;

PM2_Supporting

The variant is not found in gnomAD v4.1.0 (PM2_Supporting).

PP1

One of the patients with this variant was reported to have an affected sibling but phase was not confirmed (PMID: 16650086; PP1 not met).

PM5

no other missense variants at this position to consider

Curation History

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