Variant: NM_000070.2(CAPN3):c.223dup

CA220346

92411 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 87928b1c-f1fb-4823-bed7-a7d20c0f6cf4

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000070.2(CAPN3):c.223dup
NC_000015.10:g.42360028dup
CM000677.2:g.42360028dup
NC_000015.9:g.42652226dup
CM000677.1:g.42652226dup
NC_000015.8:g.40439518dup
NG_008660.1:g.16926dup
ENST00000349748.8:c.223dup
ENST00000357568.8:c.223dup
ENST00000397163.8:c.223dup
ENST00000466369.5:n.540+5575dup
ENST00000483208.5:n.540+5575dup
ENST00000495723.1:n.540+5575dup
ENST00000549793.5:n.540+5575dup
ENST00000318023.11:c.223dup
ENST00000349748.7:c.223dup
ENST00000357568.7:c.223dup
ENST00000397163.7:c.223dup
NM_000070.2:c.223dup
NM_024344.1:c.223dup
NM_173087.1:c.223dup
NM_000070.3:c.223dup
NM_024344.2:c.223dup
NM_173087.2:c.223dup

Pathogenic

• Met criteria codes: PM3_Supporting PM2_Supporting PVS1 PP4

• Not Met criteria codes: BS3 BS1 BS2 BP5 BP7 BP3 BP4 BP1 BA1 PM1 PM4 PM5 PS4 PS2 PS3 PS1 PM6 PP3 PP2

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.223dup p.(Tyr75LeufsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least four individuals with LGMD (PMID: 27854218, 30564623; LOVD CAPN3_000537). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 0.5 pts, LOVD Individual #00220184) (PM3_Supporting), and at least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). 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): PVS1, PM3_Supporting, PP4, PM2_Supporting.

Met criteria codes

• PM3_Supporting: This variant has been detected in at least four individuals with LGMD (PMID: 27854218, 30564623; LOVD CAPN3_000537). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 0.5 pts) (PM3_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).
• PVS1: The c.223dup p.(Tyr75LeufsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4).

Not Met criteria codes

• 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
• 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
• 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
• BA1: 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
• PM5: 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
• PS2: 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
• PS1: 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
• PP3: 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