Evidence Repository - Clinical Genome Resources

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Variant: NM_000070.3(CAPN3):c.1336G>A (p.Gly446Ser)

CA10604779

284385 (ClinVar)

Gene: CAPN3 (HGNC:825)

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

Inheritance Mode: Autosomal recessive inheritance

UUID: c5914cff-94c5-4f73-83bf-512bba9c7d62

Approved on: 2026-04-28

Published on: 2026-05-07

HGVS expressions

NM_000070.3:c.1336G>A

NM_000070.3(CAPN3):c.1336G>A (p.Gly446Ser)

NC_000015.10:g.42399634G>A

CM000677.2:g.42399634G>A

NC_000015.9:g.42691832G>A

CM000677.1:g.42691832G>A

NC_000015.8:g.40479124G>A

NG_008660.1:g.56532G>A

ENST00000349748.8:c.1192G>A

ENST00000357568.8:c.1336G>A

ENST00000397163.8:c.1336G>A

ENST00000466369.5:n.1845G>A

ENST00000483208.5:n.1567G>A

ENST00000495723.1:n.1567G>A

ENST00000549793.5:n.1567G>A

ENST00000638141.2:n.1207G>A

ENST00000673658.1:n.320G>A

ENST00000673705.1:c.291G>A

ENST00000318023.11:c.1192G>A

ENST00000349748.7:c.1192G>A

ENST00000357568.7:c.1336G>A

ENST00000397163.7:c.1336G>A

NM_000070.2:c.1336G>A

NM_024344.1:c.1336G>A

NM_173087.1:c.1192G>A

NM_024344.2:c.1336G>A

NM_173087.2:c.1192G>A

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2_Supporting

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.1336G>A variant in CAPN3 is a missense variant predicted to cause the substitution of glycine by serine at amino acid position 446, p.(Gly446Ser). This variant has been identified in at least four patients with clinical signs of LGMD, including in a homozygous state (0.5 pts, PMID: 22443334) and confirmed in trans with a likely pathogenic or pathogenic variant (c.883_886delinsCTT p.(Asp295_Asn296delinsLeufsTer57), 1.0 pt, PMID: 30919934, LOVD Individual #00214368) (PM3). In the two other patients, a second presumed diagnostic CAPN3 variant was not identified (PMID: 18337726; GRASP-LGMD Consortium internal data communication). The patient homozygous for this variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 22443334; PP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.99, 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 Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/28/2026): PM3, PP4_Moderate, PM2_Supporting, PP3.

PP4_Moderate

A patient homozygous for this variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 22443334; PP4_Moderate). LGMD with progressive muscle weakness, 15% control calpain-3 expression on WB.

PP3

The computational predictor REVEL gives a score of 0.99, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). spliceAI 0, not in a splice region

PM3

This variant has been identified in at least four patients with clinical signs of LGMD, including in a homozygous state (0.5 pts, PMID: 22443334) and confirmed in trans with a likely pathogenic or pathogenic variant (c.883_886delinsCTT p.(Asp295_Asn296delinsLeufsTer57), 1.0 pt, PMID: 30919934, LOVD Individual #00214368) (PM3). In the two other patients, a second presumed diagnostic CAPN3 variant was not identified (PMID: 18337726; GRASP-LGMD Consortium internal data communication). VUS by Labcorp, unknown affected status, suggesting they do not have internal cases

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PM5

no other missense changes at this residue in ClinVar or LOVD.

Curation History

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