Variant: NM_000070.3(CAPN3):c.633G>C (p.Lys211Asn)

CA10604967

284946 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: d6ad0238-1324-4d4a-8b8e-1820bc8b1a69

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000070.3:c.633G>C
NM_000070.3(CAPN3):c.633G>C (p.Lys211Asn)
NC_000015.10:g.42388928G>C
CM000677.2:g.42388928G>C
NC_000015.9:g.42681126G>C
CM000677.1:g.42681126G>C
NC_000015.8:g.40468418G>C
NG_008660.1:g.45826G>C
ENST00000349748.8:c.633G>C
ENST00000357568.8:c.633G>C
ENST00000397163.8:c.633G>C
ENST00000466369.5:n.1142G>C
ENST00000483208.5:n.864G>C
ENST00000495723.1:n.864G>C
ENST00000549793.5:n.864G>C
ENST00000638141.2:n.648G>C
ENST00000673705.1:c.70+4376G>C
ENST00000318023.11:c.633G>C
ENST00000349748.7:c.633G>C
ENST00000357568.7:c.633G>C
ENST00000397163.7:c.633G>C
NM_000070.2:c.633G>C
NM_024344.1:c.633G>C
NM_173087.1:c.633G>C
NM_024344.2:c.633G>C
NM_173087.2:c.633G>C

Likely Pathogenic

• Met criteria codes: PP4_Strong PP3 PM3_Supporting PM2_Supporting

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1 PS2 PS4 PS1 PS3 BA1 PP1 PP2 PM5 PM1 PM4 PM6 PVS1

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.633G>C variant in CAPN3 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 211 (p.Lys211Asn). This variant has been detected in at least nine individuals with limb girdle muscular dystrophy (PMID: 16411092, 20694146, 18055493, 18334579, 16141003, 30564623; LOVD CAPN3_000437; Washington University internal clinic data communication), including two observations in unknown phase with a variant classified as at least likely pathogenic (c.1319G>A p.(Arg440Gln), 0.5 pts, PMID: 18334579, 18055493, 20694146). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 20694146). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.859, which is above the 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 (LGMD VCEP specifications version 1.0.0; 01/07/2025): PM3_Supporting, PP4_Strong, PM2_Supporting, PP3.

Met criteria codes

• PP4_Strong: At least one patient with this variant displayed progressive limb girdle muscle weakness and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 20694146).
• PP3: The computational predictor REVEL gives a score of 0.859, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3).
• PM3_Supporting: This variant has been detected in at least nine individuals with limb girdle muscular dystrophy (PMID: 16411092, 20694146, 18055493, 18334579, 16141003, 30564623; LOVD CAPN3_000437; Washington University internal data), including two observations in unknown phase with a variant classified as at least likely pathogenic (c.1319G>A p.(Arg440Gln), 0.5 pts, PMID: 18334579, 18055493, 20694146).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting).

Not Met criteria codes

• 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
• BS2: 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
• BP5: 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
• BP3: 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
• 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
• PS1: 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: 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
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: 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
• PM6: 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