Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: CAPN3 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000070.3(CAPN3):c.598_612del (p.Phe200_Leu204del)

CA346121

166786 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 6e79984d-e8df-4824-9a7c-7f353d9a640e
Approved on: 2025-03-18
Published on: 2025-04-04

HGVS expressions

NM_000070.3:c.598_612del
NM_000070.3:c.598_612delTTCTGGAGTGCTCTG
NM_000070.3(CAPN3):c.598_612del (p.Phe200_Leu204del)
NC_000015.10:g.42387852_42387866del
CM000677.2:g.42387852_42387866del
NC_000015.9:g.42680050_42680064del
CM000677.1:g.42680050_42680064del
NC_000015.8:g.40467342_40467356del
NG_008660.1:g.44750_44764del
ENST00000349748.8:c.598_612del
ENST00000357568.8:c.598_612del
ENST00000397163.8:c.598_612del
ENST00000466369.5:n.1107_1121del
ENST00000483208.5:n.829_843del
ENST00000495723.1:n.829_843del
ENST00000549793.5:n.829_843del
ENST00000638141.2:n.613_627del
ENST00000673705.1:c.70+3300_70+3314del
ENST00000318023.11:c.598_612del
ENST00000349748.7:c.598_612del
ENST00000357568.7:c.598_612del
ENST00000397163.7:c.598_612del
NM_000070.2:c.598_612del
NM_024344.1:c.598_612del
NM_173087.1:c.598_612del
NM_024344.2:c.598_612del
NM_173087.2:c.598_612del
More

Pathogenic

Met criteria codes 4
PP4_Strong PM2_Supporting PM4 PM3_Very Strong

Evidence Links 0

Expert Panel

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.598_612del variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of five amino acids in a non-repeat region, p.(Phe200_Leu204del) (PM4). This variant has been detected in at least 24 individuals with LGMD2A (PMID: 23821418, 34720847, 25135358, 34863162, 37688281,16372320, 30564623). At least six patients were compound heterozygous for c.598_612del and a pathogenic variant (c.550del or c.1746-20C>G, 6.0 pts, PMID: 16372320, 23821418, 34720847), and three patients were homozygous (1.0 pt, PMID: 23821418) (PM3_Very Strong). At least one patient with this variant and a second CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly consistent with CAPN3-related LGMD (PMID: 16372320; PP4_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 20/1112002 exome chromosomes) is 0.000026 for the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (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; 03/18/2025): PM4, PM3_Very Strong, PP4_Strong, PM2_Supporting.
Met criteria codes
PP4_Strong
At least one patient with this variant and a second CAPN3 variant had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PMID: 16372320; PP4_Strong). In PMID: 34720847, two unrelated patients with a compound heterozygous genotype for c.598_612del and c.1746-20C>G were observed. Western blotting revealed a significant reduction or absence of calpain-3, particularly in compound heterozygotes with the c.1746-20C>G variant, further supporting the pathogenicity of these variants. In PMID: 16372320, the absence of calpain-3 protein was confirmed in both Patient 5 and Patient 10, consistent with the clinical diagnosis of LGMD2A. Patient 5 had c.1746-20C>G in trans.
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 20/1112002 exome chromosomes) is 0.000026 for the European (non-Finnish) population in gnomAD v4.1.0, which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
PM4
The NM_000070.3: c.598_612del variant in CAPN3 is predicted to cause a change in the length of the protein due to an in-frame deletion of five amino acids in a non-repeat region, p.(Phe200_Leu204del) (PM4).
PM3_Very Strong
This variant has been detected in at least 24 individuals with LGMD2A (PMID: 23821418, 34720847, 25135358, 34863162, 37688281,16372320, 30564623). At least six patients were compound heterozygous for c.598_612del and a pathogenic variant (c.550del or c.1746-20C>G, 6.0 pts, PMID: 16372320, 23821418, 34720847), and three patients were homozygous (1.0 pt, PMID: 23821418) (PM3_Very Strong).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.