Variant: NM_000070.3(CAPN3):c.1469G>A (p.Arg490Gln)

CA341479

17622 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: d235fd78-cdd6-4aed-9d55-bc0a90ba72ce

Approved on: 2025-01-09

Published on: 2025-01-09

HGVS expressions

NM_000070.3:c.1469G>A
NM_000070.3(CAPN3):c.1469G>A (p.Arg490Gln)
NC_000015.10:g.42401755G>A
CM000677.2:g.42401755G>A
NC_000015.9:g.42693953G>A
CM000677.1:g.42693953G>A
NC_000015.8:g.40481245G>A
NG_008660.1:g.58653G>A
ENST00000349748.8:c.1325G>A
ENST00000357568.8:c.1469G>A
ENST00000397163.8:c.1469G>A
ENST00000466369.5:n.1978G>A
ENST00000483208.5:n.1700G>A
ENST00000495723.1:n.1700G>A
ENST00000549793.5:n.1700G>A
ENST00000638141.2:n.1340G>A
ENST00000673705.1:c.309+2103G>A
ENST00000318023.11:c.1325G>A
ENST00000349748.7:c.1325G>A
ENST00000357568.7:c.1469G>A
ENST00000397163.7:c.1469G>A
NM_000070.2:c.1469G>A
NM_024344.1:c.1469G>A
NM_173087.1:c.1325G>A
NM_024344.2:c.1469G>A
NM_173087.2:c.1325G>A

Pathogenic

• Met criteria codes: PM3_Very Strong PM5 PP4 PP3

• Not Met criteria codes: PM2

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 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_000070.3: c.1469G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 490 (p.Arg440Gln). This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID: 26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID: 18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID: 26404900, 18854869, 22378277) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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_Very Strong, PP4, PP3, PM5.

Met criteria codes

• PM3_Very Strong: This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID: 26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID: 18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID: 26404900, 18854869, 22378277) (PM3_Very Strong).
• PM5: Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5).
• PP4: At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4).
• PP3: The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3).

Not Met criteria codes

• PM2: The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met).