Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000070.3(CAPN3):c.2393C>A (p.Ala798Glu)

CA220348

92414 (ClinVar)

Gene: CAPN3 (HGNC:825)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: ce4d1700-8d2f-43d4-b2db-a351e5aaa75d

Approved on: 2026-02-18

Published on: 2026-04-09

HGVS expressions

NM_000070.3(CAPN3):c.2393C>A (p.Ala798Glu)

NM_000070.3:c.2393C>A

NC_000015.10:g.42411299C>A

CM000677.2:g.42411299C>A

NC_000015.9:g.42703497C>A

CM000677.1:g.42703497C>A

NC_000015.8:g.40490789C>A

NG_008660.1:g.68197C>A

ENST00000337571.9:c.398C>A

ENST00000349748.8:c.2117C>A

ENST00000357568.8:c.2375C>A

ENST00000397163.8:c.2393C>A

ENST00000397204.9:c.398C>A

ENST00000466222.7:n.764C>A

ENST00000466369.5:n.2884C>A

ENST00000495723.1:n.3264C>A

ENST00000549793.5:n.2606C>A

ENST00000562199.2:c.397C>A

ENST00000567817.6:c.182C>A

ENST00000568153.2:c.259C>A

ENST00000569136.6:c.398C>A

ENST00000638141.2:n.2132C>A

ENST00000673646.1:c.957C>A

ENST00000673684.1:n.375C>A

ENST00000673692.1:c.398C>A

ENST00000673705.1:c.1222C>A

ENST00000673743.1:c.296C>A

ENST00000673750.1:c.398C>A

ENST00000673771.1:c.398C>A

ENST00000673774.1:n.1526C>A

ENST00000673839.1:c.398C>A

ENST00000673851.1:c.398C>A

ENST00000673854.1:n.5815C>A

ENST00000673886.1:c.398C>A

ENST00000673890.1:c.398C>A

ENST00000673928.1:c.398C>A

ENST00000673936.1:c.398C>A

ENST00000673939.1:c.*113C>A

ENST00000673950.1:n.667C>A

ENST00000673978.1:c.536C>A

ENST00000673987.1:c.*113C>A

ENST00000674011.1:c.*187C>A

ENST00000674018.1:c.398C>A

ENST00000674027.1:n.544C>A

ENST00000674041.1:c.398C>A

ENST00000674052.1:c.617C>A

ENST00000674093.1:c.398C>A

ENST00000674119.1:c.398C>A

ENST00000674135.1:c.575C>A

ENST00000674139.1:c.398C>A

ENST00000674146.1:c.398C>A

ENST00000674149.1:c.398C>A

ENST00000318023.11:c.2249C>A

ENST00000337571.8:c.398C>A

ENST00000349748.7:c.2117C>A

ENST00000356316.7:c.398C>A

ENST00000357568.7:c.2375C>A

ENST00000397163.7:c.2393C>A

ENST00000397200.8:c.857C>A

ENST00000397204.8:c.398C>A

ENST00000466222.6:n.1316C>A

ENST00000561817.5:c.398C>A

ENST00000564503.5:c.436C>A

ENST00000565274.5:c.571C>A

ENST00000567817.5:c.209C>A

ENST00000568153.1:c.130C>A

ENST00000569136.5:c.398C>A

ENST00000569827.5:c.725C>A

NM_000070.2:c.2393C>A

NM_024344.1:c.2375C>A

NM_173087.1:c.2117C>A

NM_173088.1:c.857C>A

NM_173089.1:c.398C>A

NM_173090.1:c.398C>A

NM_024344.2:c.2375C>A

NM_173087.2:c.2117C>A

NM_173088.2:c.857C>A

NM_173089.2:c.398C>A

NM_173090.2:c.398C>A

Pathogenic

PP4_Strong PM3_Very Strong

BA1 BP4 BS1 PP3 PM2

Evidence Links 0

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000070.3: c.2393C>A variant in CAPN3 is a missense variant predicted to cause substitution of alanine by glutamic acid at amino acid 798, p.(Ala798Glu). This variant has been detected in at least 10 individuals with features consistent with limb girdle muscular dystrophy (PMID: 38794994, 37526466, 31555977, 19556129, 30919934), including in a homozygous state without reported consanguinity in one patient (0.5 pts, PMID: 31555977), in unconfirmed phase with a pathogenic variant in two patients (c.598_612del p.(Phe200_Leu204del), 0.5pts, PMID: 38794994; c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 38794994), and confirmed in trans with a pathogenic variant in four patients (c.550del p.(Thr184Argfs36),1 pt, PMID: 37526466; c.1194-9A>G,1 pt, PMID: 37526466; c.1621C>T p.(Arg541Trp), 1 pt, PMID: 19556129; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14),1 pt, PMID: 30919934) (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 calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 19556129). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0002868 (308/1179972 European (non-Finnish) exome and genome chromosomes), which is greater than the ClinGen LGMD VCEP threshold <0.0001 for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.687, which is less than the Clingen LGMD VCEP threshold of ≥0.7. 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 (specifications version 2.0.0; 02/18/2026): PM3_VeryStrong, PP4_Strong.

PP4_Strong

At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18055493, 19556129).

PM3_Very Strong

This variant has been detected in at least 10 individuals with features consistent with limb girdle muscular dystrophy (PMID: 38794994, 37526466, 31555977, 19556129, 30919934), including in a homozygous state without reported consanguinity in one patient (0.5 pts, PMID: 31555977), in unconfirmed phase with a pathogenic variant in two patients (c.598_612del p.(Phe200_Leu204del), 0.5pts, PMID: 38794994; c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 38794994), and confirmed in trans with a pathogenic variant in four patients (c.550del p.(Thr184Argfs36),1 pt, PMID: 37526466; c.1194-9A>G,1 pt, PMID: 37526466; c.1621C>T p.(Arg541Trp), 1 pt, PMID: 19556129; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14),1 pt, PMID: 30919934) (PM3_Very Strong).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

The computational predictor REVEL gives a score of 0.687, which is greater than the Clingen LGMD VCEP threshold of ≥0.1.

BS1

The filtering allele frequency of this variant is 0.0002367 (the lower threshold of the 95% CI of 308/1179972 exomes and genome chromosomes) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold >0.001 for BS1.

PP3

The computational predictor REVEL gives a score of 0.687, which is less than the Clingen LGMD VCEP threshold of ≥0.7.

PM2

The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0002868 (308/1179972 European (non-Finnish) exome and genome chromosomes), which is greater than the ClinGen LGMD VCEP threshold <0.0001 for PM2_Supporting (criterion not met).

Curation History

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