Variant: NM_000070.3(CAPN3):c.1256A>G (p.Asp419Gly)

CA10604828

284518 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: e1096c5e-9eb9-40e7-87b5-1de5084d1a17

Approved on: 2025-01-07

Published on: 2025-01-07

HGVS expressions

NM_000070.3:c.1256A>G
NM_000070.3(CAPN3):c.1256A>G (p.Asp419Gly)
NC_000015.10:g.42399554A>G
CM000677.2:g.42399554A>G
NC_000015.9:g.42691752A>G
CM000677.1:g.42691752A>G
NC_000015.8:g.40479044A>G
NG_008660.1:g.56452A>G
ENST00000349748.8:c.1112A>G
ENST00000357568.8:c.1256A>G
ENST00000397163.8:c.1256A>G
ENST00000466369.5:n.1765A>G
ENST00000483208.5:n.1487A>G
ENST00000495723.1:n.1487A>G
ENST00000549793.5:n.1487A>G
ENST00000638141.2:n.1127A>G
ENST00000673658.1:n.240A>G
ENST00000673705.1:c.211A>G
ENST00000318023.11:c.1112A>G
ENST00000349748.7:c.1112A>G
ENST00000357568.7:c.1256A>G
ENST00000397163.7:c.1256A>G
NM_000070.2:c.1256A>G
NM_024344.1:c.1256A>G
NM_173087.1:c.1112A>G
NM_024344.2:c.1256A>G
NM_173087.2:c.1112A>G

Likely Pathogenic

• Met criteria codes: PM3_Strong PM5_Supporting PP4 PP3 PM2_Supporting

• Not Met criteria codes: PM1 PM4 BA1 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1 PS2 PS4 PS3 PS1 PP1 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.1256A>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 419 (p.Asp419Gly). This variant has been detected in at least 5 individuals with limb girdle muscular dystrophy (PMID: 18055493, 30564623, ClinVar SCV003828989.2, Washington University internal clinic data communication), including in unknown phase with a pathogenic variant (c.643_663del p.(Ser215_Gly221del), 0.5 pts, PMID: 18055493; c.756_758del p.(Lys254del) x2, 1.0 pts, PMID: 30564623; Washington University internal clinic data communication) and confirmed in trans with a likely pathogenic or pathogenic variant (c.2440-1G>A, 1.0 pt, ClinVar SCV003828989.2 internal data communication) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4; PMID: 18055493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113712 exome alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.98, which exceeds the threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1257T>G p.(Asp419Glu), has been classified as likely pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting). 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_Strong, PP4, PM2_Supporting, PP3, PM5_Supporting.

Met criteria codes

• PM3_Strong: This variant has been detected in at least 5 individuals with limb girdle muscular dystrophy (PMID: 18055493, 30564623, SCV003828989.2, Washington University clinic data), including in unknown phase with a pathogenic variant (c.643_663del p.(Ser215_Gly221del), 0.5 pts, PMID: 18055493; c.756_758del p.(Lys254del), 1.0 pts, PMID: 30564623; Washington University clinic data) and confirmed in trans with a likely pathogenic or pathogenic variant (c.2440-1G>A, 1.0 pt, SCV003828989.2) (PM3_Strong).
• PM5_Supporting: Another missense variant at the same codon, c.1257T>G p.(Asp419Glu), has been classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5_Supporting).
• PP4: At least one patient with this variant displayed progressive weakness, which is specific for LGMD 2A (PP4_Supporting, PMID: 18055493).
• PP3: The computational predictor REVEL gives a score of 0.98, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008 (1/113712 exome alleles) in the European (non-Finnish) population, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting)

Not Met criteria codes

• 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
• BA1: 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
• 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
• 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
• 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
• PVS1: 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
• PS1: 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