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.1993-1G>A

CA7511659

282494 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: ff55c161-a1d6-4397-a169-84ccb21b6a9b
Approved on: 2025-05-03
Published on: 2025-06-06

HGVS expressions

NM_000070.3:c.1993-1G>A
NM_000070.3(CAPN3):c.1993-1G>A
NC_000015.10:g.42409786G>A
CM000677.2:g.42409786G>A
NC_000015.9:g.42701984G>A
CM000677.1:g.42701984G>A
NC_000015.8:g.40489276G>A
NG_008660.1:g.66684G>A
ENST00000337571.9:c.-3-1G>A
ENST00000349748.8:c.1717-1G>A
ENST00000357568.8:c.1975-1G>A
ENST00000397163.8:c.1993-1G>A
ENST00000397204.9:c.-3-1G>A
ENST00000466222.7:n.258-1G>A
ENST00000466369.5:n.2484-1G>A
ENST00000495723.1:n.2864-1G>A
ENST00000549793.5:n.2206-1G>A
ENST00000569136.6:c.-3-1G>A
ENST00000638141.2:n.1732-1G>A
ENST00000673646.1:c.557-1G>A
ENST00000673687.1:n.70-1G>A
ENST00000673692.1:c.-3-1G>A
ENST00000673705.1:c.388-1G>A
ENST00000673743.1:c.-100-1G>A
ENST00000673750.1:c.-3-1G>A
ENST00000673771.1:c.-3-1G>A
ENST00000673774.1:n.693G>A
ENST00000673839.1:c.-3-1G>A
ENST00000673851.1:c.-3-1G>A
ENST00000673854.1:n.5415-1G>A
ENST00000673886.1:c.-3-1G>A
ENST00000673890.1:c.-3-1G>A
ENST00000673928.1:c.-3-1G>A
ENST00000673936.1:c.-3-1G>A
ENST00000673939.1:c.-3-1G>A
ENST00000673950.1:n.267-1G>A
ENST00000673978.1:c.136-1G>A
ENST00000673987.1:c.-3-1G>A
ENST00000674011.1:c.-3-1G>A
ENST00000674018.1:c.-3-1G>A
ENST00000674027.1:n.53-1G>A
ENST00000674041.1:c.-3-1G>A
ENST00000674052.1:c.217-1G>A
ENST00000674093.1:c.-3-1G>A
ENST00000674119.1:c.-3-1G>A
ENST00000674130.1:n.210G>A
ENST00000674135.1:c.175-1G>A
ENST00000674139.1:c.-3-1G>A
ENST00000674146.1:c.-3-1G>A
ENST00000674149.1:c.-3-1G>A
ENST00000318023.11:c.1849-1G>A
ENST00000337571.8:c.-3-1G>A
ENST00000349748.7:c.1717-1G>A
ENST00000356316.7:c.-3-1G>A
ENST00000357568.7:c.1975-1G>A
ENST00000397163.7:c.1993-1G>A
ENST00000397200.8:c.457-1G>A
ENST00000397204.8:c.-3-1G>A
ENST00000466222.6:n.916-1G>A
ENST00000561817.5:c.-3-1G>A
ENST00000564503.5:c.90-1G>A
ENST00000565274.5:c.205-1G>A
ENST00000565559.5:c.175-1G>A
ENST00000567071.5:c.473-1G>A
ENST00000569136.5:c.-3-1G>A
ENST00000569827.5:c.325-1G>A
NM_000070.2:c.1993-1G>A
NM_024344.1:c.1975-1G>A
NM_173087.1:c.1717-1G>A
NM_173088.1:c.457-1G>A
NM_173089.1:c.-3-1G>A
NM_173090.1:c.-3-1G>A
NM_024344.2:c.1975-1G>A
NM_173087.2:c.1717-1G>A
NM_173088.2:c.457-1G>A
NM_173089.2:c.-3-1G>A
NM_173090.2:c.-3-1G>A
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Pathogenic

Met criteria codes 4
PM3 PP4_Moderate PVS1 PM2_Supporting

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.1993-1G>A variant in CAPN3 occurs within the -1/2 dinucleotide splice acceptor site of intron 17. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen an alternative site 1 bp away, with a SpliceAI score of 1.0. Use of the alternative acceptor site or skipping of exon 18, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated decay in a gene in which loss of function is an established mechanism of disease (PVS1). This variant has been reported in at least six patients with clinical features consistent with LGMD (PMID: 30564623, 26404900, 18055493; LOVD CAPN3_000288), including in a homozygous state in one proband from a family without reported consanguinity (0.5 pts, PMID: 30564623, LOVD Individual #00220357) and in unknown phase with a pathogenic variant in one individual (c.550del, 0.5 pts, PMID: 30564623, LOVD Individual #00219523) (PM3). At least one individual with this variant and a second presumed diagnostic variant in CAPN3 had a clinical suspicion of LGMD and significantly reduced calpain-3 protein expression on western blot, which is specific for CAPN3-related LGMD (PMID: 18055493; PP4_Moderate). The filtering allele frequency of this variant is 0.000030594 in the European (non-Finnish) population in gnomAD v4.1.0 (24/1103246 exomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting 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; 05/03/2025): PVS1, PM3, PP4_Moderate, PM2_Supporting.
Met criteria codes
PM3
This variant has been reported in at least six patients with clinical features consistent with LGMD (PMID: 30564623, 26404900, 18055493; LOVD CAPN3_000288), including in a homozygous state in one proband from a family without reported consanguinity (0.5 pts, PMID: 30564623, LOVD Individual #00220357) and in unknown phase with a pathogenic variant in one individual (c.550del, 0.5 pts, PMID: 30564623, LOVD Individual #00219523) (PM3). predicted on different haplotype with c.550del in European (non-Finnish) population, no prediction for other populations
PP4_Moderate
At least one individual with this variant and a second presumed diagnostic variant in CAPN3 had a clinical suspicion of LGMD and significantly reduced calpain-3 protein expression on western blot, which is specific for CAPN3-related LGMD (PMID: 18055493; PP4_Moderate). In PMID: 18055493, patients were referred to specialized LGMD diagnostic service, so presume clinical suspicion of LGMD. For patient 29, absent expression of 30 kDa band, expression of 94 kDa band score 2 (significantly reduced). c.566T>C p.(Leu189Pro) in unknown phase: not yet curated but presumed diagnostic.
PVS1
The NM_000070.3: c.1993-1G>A variant in CAPN3 occurs within the -1/2 dinucleotide splice acceptor site of intron 17. This variant is predicted to abolish the consensus splice acceptor site, with a SpliceAI score of 0.99, and strengthen an alternative site 1 bp downstream, with a SpliceAI score of 1.0. Use of the alternative acceptor site or skipping of exon 18, which is out of frame, would be expected to disrupt the reading frame, leading to nonsense mediated decay in a gene in which loss of function is an established mechanism of disease (PVS1).
PM2_Supporting
The filtering allele frequency of this variant is 0.000030594 in the European (non-Finnish) population in gnomAD v4.1.0 (24/1103246 exome chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
Curation History
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