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.2306G>A (p.Arg769Gln)

CA127306

17613 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f1a2c1a0-76fc-4e97-873f-3b47fb3f5aaf
Approved on: 2025-04-22
Published on: 2025-05-16

HGVS expressions

NM_000070.3:c.2306G>A
NM_000070.3(CAPN3):c.2306G>A (p.Arg769Gln)
NC_000015.10:g.42410926G>A
CM000677.2:g.42410926G>A
NC_000015.9:g.42703124G>A
CM000677.1:g.42703124G>A
NC_000015.8:g.40490416G>A
NG_008660.1:g.67824G>A
ENST00000337571.9:c.311G>A
ENST00000349748.8:c.2030G>A
ENST00000357568.8:c.2288G>A
ENST00000397163.8:c.2306G>A
ENST00000397204.9:c.311G>A
ENST00000466222.7:n.751G>A
ENST00000466369.5:n.2797G>A
ENST00000495723.1:n.3177G>A
ENST00000549793.5:n.2519G>A
ENST00000562199.2:c.310G>A
ENST00000567817.6:c.95G>A
ENST00000568153.2:c.172G>A
ENST00000569136.6:c.311G>A
ENST00000638141.2:n.2045G>A
ENST00000673646.1:c.870G>A
ENST00000673684.1:n.288G>A
ENST00000673692.1:c.311G>A
ENST00000673705.1:c.849G>A
ENST00000673743.1:c.209G>A
ENST00000673750.1:c.311G>A
ENST00000673771.1:c.311G>A
ENST00000673774.1:n.1439G>A
ENST00000673839.1:c.311G>A
ENST00000673851.1:c.311G>A
ENST00000673854.1:n.5728G>A
ENST00000673886.1:c.311G>A
ENST00000673890.1:c.311G>A
ENST00000673928.1:c.311G>A
ENST00000673936.1:c.311G>A
ENST00000673939.1:c.*100G>A
ENST00000673950.1:n.580G>A
ENST00000673978.1:c.449G>A
ENST00000673987.1:c.*100G>A
ENST00000674011.1:c.*100G>A
ENST00000674018.1:c.311G>A
ENST00000674027.1:n.457G>A
ENST00000674041.1:c.311G>A
ENST00000674052.1:c.530G>A
ENST00000674093.1:c.311G>A
ENST00000674119.1:c.311G>A
ENST00000674135.1:c.488G>A
ENST00000674139.1:c.311G>A
ENST00000674146.1:c.311G>A
ENST00000674149.1:c.311G>A
ENST00000318023.11:c.2162G>A
ENST00000337571.8:c.311G>A
ENST00000349748.7:c.2030G>A
ENST00000356316.7:c.311G>A
ENST00000357568.7:c.2288G>A
ENST00000397163.7:c.2306G>A
ENST00000397200.8:c.770G>A
ENST00000397204.8:c.311G>A
ENST00000466222.6:n.1229G>A
ENST00000561817.5:c.311G>A
ENST00000562199.1:n.310G>A
ENST00000564503.5:c.349G>A
ENST00000565274.5:c.484G>A
ENST00000567817.5:c.122G>A
ENST00000568153.1:c.43G>A
ENST00000569136.5:c.311G>A
ENST00000569827.5:c.638G>A
NM_000070.2:c.2306G>A
NM_024344.1:c.2288G>A
NM_173087.1:c.2030G>A
NM_173088.1:c.770G>A
NM_173089.1:c.311G>A
NM_173090.1:c.311G>A
NM_024344.2:c.2288G>A
NM_173087.2:c.2030G>A
NM_173088.2:c.770G>A
NM_173089.2:c.311G>A
NM_173090.2:c.311G>A
More

Pathogenic

Met criteria codes 5
PP4 PP3 PM3 PM2_Supporting PP1_Strong
Not Met criteria codes 4
PS3 PM5 PVS1 BP7

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.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID: 14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID: 12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID: 32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence.
Met criteria codes
PP4
At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 14645990; PP4 (capped with PP1_Strong)).
PP3
The computational predictor Revel gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI score of 0.49 for donor loss, but minigene assay suggest splice impact negligible, if any.
PM3
The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID: 14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). ~34 total homozygous cases in LOVD, especially from Nallamilli et al.; these cannot be awarded points given the cap on homozygosity at 1 pt.
PM2_Supporting
The filtering allele frequency of this variant is 0.000089887 (the upper threshold of the 95% CI of 3/86258 South Asian exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).
PP1_Strong
This variant was observed to segregate with autosomal recessive LGMD in 8 affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID: 12461690, 7720071; PP1_Strong).
Not Met criteria codes
PS3
In an in vitro assay, cells expressing this variant showed severely reduced calpain-3 protein expression on Western blot, indicating that this variant impacts protein function (PMID: 9642272). No approved functional assays for calpain-3 (PS3 not met).
PM5
c.2306G>C (p.Arg769Pro) preliminarily curated (currently VUS). Both c.2306G>C and G>A have SpliceAI scores above the threshold of 0.1, so PM5 cannot be considered under current specification guidelines, even if we consider mini-gene assay as evidence of normal splicing for G>A.
PVS1
Minigene assay suggested a possible mild impact on splicing (possible loss of a minor non-canonical natural splice form with a shortened exon 22 containing only the first 43 nt), but a largely preserved expression of transcripts with normal splicing (PMID: 32668095; PVS1_RNA not met). SpliceAI gives a donor loss of 0.49 at the location of this variant, which is 1/3 of the way into exon 22. VCEP consensus that the possible mild splice effect suggested on minigene assay looks non-significant. High Revel score (0.94), PP3 currently applied. If we consider minigene assay as evidence of no splice impact, BP7_Strong_RNA would not apply because cannot exclude protein impact.
BP7
Even if we consider minigene assay as evidence of no splice impact, BP7_Strong_RNA would not apply because cannot exclude protein impact with high REVEL score.
Curation History
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