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 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.1524G>A (p.Glu508=)

CA10605515

286592 (ClinVar)

Gene: CAPN3
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4e074784-84ce-4699-95c1-9966ae667481
Approved on: 2025-01-07
Published on: 2025-01-07

HGVS expressions

NM_000070.3:c.1524G>A
NM_000070.3(CAPN3):c.1524G>A (p.Glu508=)
NC_000015.10:g.42401810G>A
CM000677.2:g.42401810G>A
NC_000015.9:g.42694008G>A
CM000677.1:g.42694008G>A
NC_000015.8:g.40481300G>A
NG_008660.1:g.58708G>A
ENST00000349748.8:c.1380G>A
ENST00000357568.8:c.1524G>A
ENST00000397163.8:c.1524G>A
ENST00000466369.5:n.2033G>A
ENST00000483208.5:n.1755G>A
ENST00000495723.1:n.1755G>A
ENST00000549793.5:n.1755G>A
ENST00000638141.2:n.1395G>A
ENST00000673705.1:c.309+2158G>A
ENST00000318023.11:c.1380G>A
ENST00000349748.7:c.1380G>A
ENST00000357568.7:c.1524G>A
ENST00000397163.7:c.1524G>A
NM_000070.2:c.1524G>A
NM_024344.1:c.1524G>A
NM_173087.1:c.1380G>A
NM_024344.2:c.1524G>A
NM_173087.2:c.1380G>A
More

Pathogenic

Met criteria codes 4
PP3 PM2_Supporting PP4_Strong PM3_Strong
Not Met criteria codes 22
BP5 BP7 BP3 BP2 BP4 BP1 PS4 PS2 PS3 PS1 PP1 PP2 PM1 PM4 PM5 PM6 BA1 BS2 PVS1 BS4 BS3 BS1

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.1524G>A variant in CAPN3 is a synonymous (silent) variant (p.Glu508=) that affects the last nucleotide of exon 11. This variant has been detected in at least seven individuals with LGMD (PMID: 26404900, 17236769, 17994539, 16141003, 32528171; ClinVar SCV001423802.2 internal data communication). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID: 17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID: 17994539) (PM3_Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 protein, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769). This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting). The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 and suggestive of an impact on splicing (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; 01/07/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3.
Met criteria codes
PP3
The SpliceAI prediction score for this variant is 0.66 (donor loss), which is greater than the VCEP threshold of ≥ 0.50 (PP3). SG: donor site loss predicted with delta SpliceAI score of 0.66, above the threshold score ≥ 0.50.
PM2_Supporting
This variant is absent from gnomAD v2.1.1 and v.3.1.2 (PM2_Supporting).
PP4_Strong
At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3 which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 17236769).
PM3_Strong
This variant has been detected in at least seven individuals with LGMD (PMID: 26404900, 17236769, 17994539, 16141003, 32528171; SCV001423802.2). Of those individuals, at least three were compound heterozygous, and in at least two, the variant was confirmed in trans with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 2.0 pts, PMID: 17236769, 17994539). In addition, at least one individual was homozygous for the variant (0.5 pts, PMID: 17994539) (PM3_Strong).
Not Met criteria codes
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
The c.1524G>A (p.Glu508=) variant is a synonymous (silent) variant. BP7 was not applied because SpliceAI predicts an impact on splicing (donor loss score: 0.66), and the nucleotide is conserved, as shown by PhyloP (score of 9.6).
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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