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.701G>A (p.Gly234Glu)

CA16609628

501754 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
UUID: 6a245e3c-eec4-47f4-9fd5-85b38f7df103
Approved on: 2025-01-09
Published on: 2025-01-09

HGVS expressions

NM_000070.3:c.701G>A
NM_000070.3(CAPN3):c.701G>A (p.Gly234Glu)
NC_000015.10:g.42388996G>A
CM000677.2:g.42388996G>A
NC_000015.9:g.42681194G>A
CM000677.1:g.42681194G>A
NC_000015.8:g.40468486G>A
NG_008660.1:g.45894G>A
ENST00000349748.8:c.701G>A
ENST00000357568.8:c.701G>A
ENST00000397163.8:c.701G>A
ENST00000466369.5:n.1210G>A
ENST00000483208.5:n.932G>A
ENST00000495723.1:n.932G>A
ENST00000549793.5:n.932G>A
ENST00000638141.2:n.716G>A
ENST00000673705.1:c.70+4444G>A
ENST00000318023.11:c.701G>A
ENST00000349748.7:c.701G>A
ENST00000357568.7:c.701G>A
ENST00000397163.7:c.701G>A
NM_000070.2:c.701G>A
NM_024344.1:c.701G>A
NM_173087.1:c.701G>A
NM_024344.2:c.701G>A
NM_173087.2:c.701G>A
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Pathogenic

Met criteria codes 4
PP3 PM3_Strong PM2_Supporting PP4_Strong
Not Met criteria codes 1
PS3

Evidence Links 1

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.701G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 234 (p.Gly234Glu). This variant has been detected in at least 8 individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, PMID: 27500519, 17994539) and in trans with a likely pathogenic or pathogenic variant in at least one patient (c.1319G>A p.(Arg440Gln), 1.0 pt, PMID: 17994539) (PM3_Strong). At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, which exceeds the 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; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3.
Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.86, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3).
PM3_Strong
This variant has been detected in at least 8 individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, PMID: 27500519, 17994539) and in trans with a pathogenic variant in at least one patient (c.1319G>A p.(Arg440Glu), 1.0 pt, PMID: 17994539) (PM3_Strong).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting).
PP4_Strong
At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17994539).
Not Met criteria codes
PS3
Functional assays have suggested this variant reduces calpain-3 autocatalytic activity (PMID: 9642272), but the LGMD VCEP has determined that this type of assay has not yet been sufficiently validated.

Curation History
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