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 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.2242C>T (p.Arg748Ter)

CA7511779

283259 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
UUID: d6fb54e2-b3a3-46d1-bf4d-0bf57f2e3a7d
Approved on: 2025-01-09
Published on: 2025-01-09

HGVS expressions

NM_000070.3:c.2242C>T
NM_000070.3(CAPN3):c.2242C>T (p.Arg748Ter)
NC_000015.10:g.42410645C>T
CM000677.2:g.42410645C>T
NC_000015.9:g.42702843C>T
CM000677.1:g.42702843C>T
NC_000015.8:g.40490135C>T
NG_008660.1:g.67543C>T
ENST00000337571.9:c.247C>T
ENST00000349748.8:c.1966C>T
ENST00000357568.8:c.2224C>T
ENST00000397163.8:c.2242C>T
ENST00000397204.9:c.247C>T
ENST00000466222.7:n.598C>T
ENST00000466369.5:n.2733C>T
ENST00000495723.1:n.3113C>T
ENST00000549793.5:n.2455C>T
ENST00000562199.2:c.246C>T
ENST00000567817.6:c.31C>T
ENST00000568153.2:c.108C>T
ENST00000569136.6:c.247C>T
ENST00000638141.2:n.1981C>T
ENST00000673646.1:c.806C>T
ENST00000673684.1:n.224C>T
ENST00000673687.1:n.842C>T
ENST00000673692.1:c.247C>T
ENST00000673705.1:c.568C>T
ENST00000673743.1:c.145C>T
ENST00000673750.1:c.247C>T
ENST00000673771.1:c.247C>T
ENST00000673774.1:n.1375C>T
ENST00000673839.1:c.247C>T
ENST00000673851.1:c.247C>T
ENST00000673854.1:n.5664C>T
ENST00000673886.1:c.247C>T
ENST00000673890.1:c.247C>T
ENST00000673928.1:c.247C>T
ENST00000673936.1:c.247C>T
ENST00000673939.1:c.247C>T
ENST00000673950.1:n.516C>T
ENST00000673978.1:c.385C>T
ENST00000673987.1:c.247C>T
ENST00000674011.1:c.247C>T
ENST00000674018.1:c.247C>T
ENST00000674027.1:n.393C>T
ENST00000674041.1:c.247C>T
ENST00000674052.1:c.466C>T
ENST00000674093.1:c.247C>T
ENST00000674119.1:c.247C>T
ENST00000674135.1:c.424C>T
ENST00000674139.1:c.247C>T
ENST00000674146.1:c.247C>T
ENST00000674149.1:c.247C>T
ENST00000318023.11:c.2098C>T
ENST00000337571.8:c.247C>T
ENST00000349748.7:c.1966C>T
ENST00000356316.7:c.247C>T
ENST00000357568.7:c.2224C>T
ENST00000397163.7:c.2242C>T
ENST00000397200.8:c.706C>T
ENST00000397204.8:c.247C>T
ENST00000466222.6:n.1165C>T
ENST00000561817.5:c.247C>T
ENST00000562199.1:n.246C>T
ENST00000564503.5:c.285C>T
ENST00000565274.5:c.420C>T
ENST00000565559.5:c.424C>T
ENST00000567817.5:c.58C>T
ENST00000569136.5:c.247C>T
ENST00000569827.5:c.574C>T
NM_000070.2:c.2242C>T
NM_024344.1:c.2224C>T
NM_173087.1:c.1966C>T
NM_173088.1:c.706C>T
NM_173089.1:c.247C>T
NM_173090.1:c.247C>T
NM_024344.2:c.2224C>T
NM_173087.2:c.1966C>T
NM_173088.2:c.706C>T
NM_173089.2:c.247C>T
NM_173090.2:c.247C>T
More

Pathogenic

Met criteria codes 3
PM3 PP4_Moderate PVS1
Not Met criteria codes 1
PM2

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.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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; 01/09/2025): PVS1, PM3, PP4_Moderate.
Met criteria codes
PM3
This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal data). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502; Washington University internal data) (PM3). Note: c.1468C>T p.(Arg490Trp) and c.2242C>T p.(Arg748Ter) predicted to be on different haplotypes by gnomAD. Different cases scored to get both variants to P.
PP4_Moderate
At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 16971480).
PVS1
The NM_000070.3: c.2242C>T p.(Arg748Ter) variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1).
Not Met criteria codes
PM2
The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met).
Curation History
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