Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000070.3(CAPN3):c.700G>A (p.Gly234Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10604244

282623 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fa328ce8-3476-431d-87d9-30045b2b1733

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000070.3:c.700G>A

NM_000070.3(CAPN3):c.700G>A (p.Gly234Arg)

NC_000015.10:g.42388995G>A

CM000677.2:g.42388995G>A

NC_000015.9:g.42681193G>A

CM000677.1:g.42681193G>A

NC_000015.8:g.40468485G>A

NG_008660.1:g.45893G>A

ENST00000349748.8:c.700G>A

ENST00000357568.8:c.700G>A

ENST00000397163.8:c.700G>A

ENST00000466369.5:n.1209G>A

ENST00000483208.5:n.931G>A

ENST00000495723.1:n.931G>A

ENST00000549793.5:n.931G>A

ENST00000638141.2:n.715G>A

ENST00000673705.1:c.70+4443G>A

ENST00000318023.11:c.700G>A

ENST00000349748.7:c.700G>A

ENST00000357568.7:c.700G>A

ENST00000397163.7:c.700G>A

NM_000070.2:c.700G>A

NM_024344.1:c.700G>A

NM_173087.1:c.700G>A

NM_024344.2:c.700G>A

NM_173087.2:c.700G>A

Pathogenic

PM2_Supporting PP1 PP3 PP4_Strong PM5 PM3

BS2 BS4 BS3 BS1 PS1 PS2 PS4 PS3 PVS1 BP2 BP4 BP1 BP3 BP5 BP7 BA1 PP2 PM6 PM4

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000070.3: c.700G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 234 (p.Gly234Arg). This variant has been detected in at least four unrelated individuals with LGMD (PMID: 26484845, 32896923, 34720847, 37589857), including confirmed in trans and in unknown phase with a pathogenic variant (c.1746-20C>G, 1.5 pts, PMID: 34720847, 37589857) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 34720847). The variant was also reported to co-segregate with the disease in two affected family members from a single family (PP1; PMID: 37589857). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.93, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.701G>A p.(Gly234Glu), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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; 01/07/2025): PM3, PP4_Strong, PP1, PM2_Supporting, PP3, PM5.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting).

PP1

The variant was also reported to co-segregate with the disease in two affected family members from a single family (PP1; PMID: 37589857). (capped with PP4_Strong)

PP3

The computational predictor REVEL gives a score of 0.93, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3).

PP4_Strong

At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 34720847).

PM5

Another missense variant at the same codon, c.701G>A p.(Gly234Glu), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5).

PM3

This variant has been detected in at least four unrelated individuals with LGMD (PMID: 26484845, 32896923, 34720847, 37589857), including confirmed in trans and in unknown phase with a pathogenic variant (c.1746-20C>G, 1.5 pts, PMID: 34720847, 37589857) (PM3).

BS2