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.2105C>T (p.Ala702Val)

CA10604398

283099 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 6f6669bf-fd07-4ba8-9c06-cc26ea482931
Approved on: 2025-05-14
Published on: 2025-06-06

HGVS expressions

NM_000070.3:c.2105C>T
NM_000070.3(CAPN3):c.2105C>T (p.Ala702Val)
NC_000015.10:g.42409985C>T
CM000677.2:g.42409985C>T
NC_000015.9:g.42702183C>T
CM000677.1:g.42702183C>T
NC_000015.8:g.40489475C>T
NG_008660.1:g.66883C>T
ENST00000337571.9:c.110C>T
ENST00000349748.8:c.1829C>T
ENST00000357568.8:c.2087C>T
ENST00000397163.8:c.2105C>T
ENST00000397204.9:c.110C>T
ENST00000466222.7:n.370C>T
ENST00000466369.5:n.2596C>T
ENST00000495723.1:n.2976C>T
ENST00000549793.5:n.2318C>T
ENST00000562199.2:c.113C>T
ENST00000569136.6:c.110C>T
ENST00000638141.2:n.1844C>T
ENST00000673646.1:c.669C>T
ENST00000673687.1:n.182C>T
ENST00000673692.1:c.110C>T
ENST00000673705.1:c.500C>T
ENST00000673743.1:c.8C>T
ENST00000673750.1:c.110C>T
ENST00000673771.1:c.110C>T
ENST00000673774.1:n.806C>T
ENST00000673839.1:c.110C>T
ENST00000673851.1:c.110C>T
ENST00000673854.1:n.5527C>T
ENST00000673886.1:c.110C>T
ENST00000673890.1:c.110C>T
ENST00000673893.1:c.29C>T
ENST00000673928.1:c.110C>T
ENST00000673936.1:c.110C>T
ENST00000673939.1:c.110C>T
ENST00000673950.1:n.379C>T
ENST00000673978.1:c.248C>T
ENST00000673987.1:c.110C>T
ENST00000674011.1:c.110C>T
ENST00000674018.1:c.110C>T
ENST00000674027.1:n.165C>T
ENST00000674041.1:c.110C>T
ENST00000674052.1:c.329C>T
ENST00000674093.1:c.110C>T
ENST00000674119.1:c.110C>T
ENST00000674130.1:n.323C>T
ENST00000674135.1:c.287C>T
ENST00000674139.1:c.110C>T
ENST00000674146.1:c.110C>T
ENST00000674149.1:c.110C>T
ENST00000318023.11:c.1961C>T
ENST00000337571.8:c.110C>T
ENST00000349748.7:c.1829C>T
ENST00000356316.7:c.110C>T
ENST00000357568.7:c.2087C>T
ENST00000397163.7:c.2105C>T
ENST00000397200.8:c.569C>T
ENST00000397204.8:c.110C>T
ENST00000466222.6:n.1028C>T
ENST00000561817.5:c.110C>T
ENST00000562199.1:n.113C>T
ENST00000564503.5:c.202C>T
ENST00000565274.5:c.317C>T
ENST00000565559.5:c.287C>T
ENST00000569136.5:c.110C>T
ENST00000569827.5:c.437C>T
NM_000070.2:c.2105C>T
NM_024344.1:c.2087C>T
NM_173087.1:c.1829C>T
NM_173088.1:c.569C>T
NM_173089.1:c.110C>T
NM_173090.1:c.110C>T
NM_024344.2:c.2087C>T
NM_173087.2:c.1829C>T
NM_173088.2:c.569C>T
NM_173089.2:c.110C>T
NM_173090.2:c.110C>T
More

Pathogenic

Met criteria codes 4
PP3 PP4_Strong PM2_Supporting 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.2105C>T variant in CAPN3 is a missense variant expected to result in the substitution of alanine with valine at amino acid 702, p.(Ala702Val). This variant has been detected in at least 11 individuals with features consistent with LGMD (PMID: 19556129; 31937337; 35741838; 16141003; 27066573; 16650086; ClinVar SCV001218172.5 internal data communication). Five seemingly unrelated patients were homozygous, with familial consanguinity reported in four (0.25 pts x4, 0.5 pts x1, capped at 1.0 pt). Two patients had a likely pathogenic or pathogenic CAPN3 variant confirmed in trans (c.1993-1G>A, 1.0 pt, ClinVar SCV001218172.5 internal data communication; c.1981del p.(Gln660_Ile661insTer), 1.0 pt, PMID: 19556129), and two patients had a pathogenic variant in unknown phase (c.2120A>G (p.Asp707Gly), 0.5 pts, PMID: 27066573; c.2362_2363delinsTCATCT (p.Arg788SerfsTer14), 0.5 pts, PMID: 35741838) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 19556129) (PP4_Strong). The filtering allele frequency of this variant is 0.000011828 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval of 7/1111640 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.77, which is above the LGMD 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 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; 05/14/2025): PM3_Very Strong, PP4_Strong, PP3, PM2_Supporting.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.77, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function.
PP4_Strong
At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 19556129) (PP4_Strong).
PM2_Supporting
The filtering allele frequency of this variant is 0.000011828 in gnomAD v4.1.0 exomes (the upper bound of the 95% confidence interval for 7/1111640 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion.
PM3_Very Strong
This variant has been detected in at least 11 individuals with features consistent with LGMD (PMID: 19556129; 31937337; 35741838; 16141003; 27066573; 16650086; ClinVar SCV001218172.5 internal data communication). Five seemingly unrelated patients were homozygous, with familial consanguinity reported in four (0.25 x4, 0.5 x1, capped at 1.0 pt). Two patients had a likely pathogenic or pathogenic CAPN3 variant confirmed in trans (c.1993-1G>A, 1.0 pt, ClinVar SCV001218172.5 internal data communication; c.1981del p.(Gln660_Ile661insTer), 1.0 pt, PMID: 19556129), and two patients had a pathogenic variant in unknown phase (c.2120A>G (p.Asp707Gly), 0.5 pts, PMID: 27066573; c.2362_2363delinsTCATCT (p.Arg788SerfsTer14), 0.5 pts, PMID: 35741838) (PM3_Very Strong). confirmed neither variant in unknown phase predicted to be on same haplotype classification of c.2120A>G (p.Asp707Gly) as P is pending approval as BS1 exception; will be presented at April 22 2025 VCEP call
Curation History
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