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

CA10604244

282623 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

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

• Met criteria codes: PP1 PP3 PP4_Strong PM2_Supporting PM5 PM3

• Not Met criteria codes: PS1 PS2 PS4 PS3 PP2 PVS1 PM6 PM4 BA1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP4 BP1 BP3

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

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.

Met criteria codes

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

Not Met criteria codes

• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline