Variant: NM_000070.3(CAPN3):c.1194-9A>G

CA347487

217146 (ClinVar)

Gene: CAPN3

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 178af75f-ca6b-4d4f-bfd7-f21d8dce3f5d

Approved on: 2025-03-18

Published on: 2025-04-04

HGVS expressions

NM_000070.3:c.1194-9A>G
NM_000070.3(CAPN3):c.1194-9A>G
NC_000015.10:g.42399483A>G
CM000677.2:g.42399483A>G
NC_000015.9:g.42691681A>G
CM000677.1:g.42691681A>G
NC_000015.8:g.40478973A>G
NG_008660.1:g.56381A>G
ENST00000349748.8:c.1050-9A>G
ENST00000357568.8:c.1194-9A>G
ENST00000397163.8:c.1194-9A>G
ENST00000466369.5:n.1703-9A>G
ENST00000483208.5:n.1425-9A>G
ENST00000495723.1:n.1425-9A>G
ENST00000549793.5:n.1425-9A>G
ENST00000638141.2:n.1065-9A>G
ENST00000673658.1:n.178-9A>G
ENST00000673705.1:c.149-9A>G
ENST00000318023.11:c.1050-9A>G
ENST00000349748.7:c.1050-9A>G
ENST00000357568.7:c.1194-9A>G
ENST00000397163.7:c.1194-9A>G
NM_000070.2:c.1194-9A>G
NM_024344.1:c.1194-9A>G
NM_173087.1:c.1050-9A>G
NM_024344.2:c.1194-9A>G
NM_173087.2:c.1050-9A>G

Pathogenic

• Met criteria codes: PVS1 PP4 PM3 PM2_Supporting

• Not Met criteria codes: PP1

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.1194-9A>G variant in CAPN3 is located in intron 9 of 23 and is expected to disrupt the canonical splice acceptor site (SpliceAI score 0.97 for acceptor loss) and create an alternative acceptor site (SpliceAI score 1.0 for acceptor gain). RNA analysis has demonstrated a splice effect of this variant, resulting in inclusion of the last eight nucleotides of intron 9, which is expected to lead to a frameshift, premature truncation, and subsequent nonsense mediated decay (PVS1_RNA). This variant has been detected in at least 9 unrelated individuals with clinical features of limb girdle muscular dystrophy (PMID: 30564623, 22158424, 12461690, 18055493, 25135358, 10330340, 11525884; LOVD CAPN3_000088; ClinVar SCV003922313.1), including in a homozygous state (0.75 pts) (PMID: 12461690, 11525884) and in unknown phase with a pathogenic variant (c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV003922313.1 (PM3). At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PP4). The minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113748 chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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; 03/18/2025): PVS1_RNA, PM3, PP4, PM2_Supporting.

Met criteria codes

• PVS1: The NM_000070.3:c.1194-9A>G variant in CAPN3 is located in intron 9 of 23 and is expected to disrupt the canonical splice acceptor site (SpliceAI score 0.97 for acceptor loss) and create an alternative acceptor site (SpliceAI score 1.0 for acceptor gain). RNA analysis has demonstrated a splice effect of this variant, resulting in inclusion of the last eight nucleotides of intron 9, which is expected to lead to a frameshift, premature truncation, and subsequent nonsense mediated decay (PVS1_RNA). Note: The patients from whom tissue was collected for RNA analysis also had the insertion of 3 Alu elements into intron 7, which is predicted to disrupt intronic splicing regulatory elements, resulting in the deletion of exons 1-7 observed on transcript analysis. Because of the complication of the Alu insertion, this family was not scored for PM3, PP1, or PP4, but the experimental demonstration of the splice impact of the c.1194-9A>G variant seems like it should still stand.
• PP4: At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PP4). Note: Patient 2, who is homozygous, described by Salem et al. (PMID: 22158424) meets the criteria for PP4_Strong: progressive limb girdle muscle weakness and absent calpain-3 protein expression, but all 3 patients in this family also had the insertion of 3 Alu elements into intron 7, which is predicted to disrupt intronic splicing regulatory elements, resulting in the deletion of exons 1-7 observed on transcript analysis. Because of the complication of the Alu insertion, this family was not scored for PM3, PP1, or PP4.
• PM3: This variant has been detected in at least 9 unrelated individuals with clinical features of limb girdle muscular dystrophy (PMID: 30564623, 22158424, 12461690, 18055493, 25135358, 10330340, 11525884; LOVD CAPN3_000088; ClinVar SCV003922313.1), including in a homozygous state (0.75 pts) (PMID: 12461690, 11525884) and in unknown phase with a pathogenic variant (c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV003922313.1 (PM3).
• PM2_Supporting: The minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113748 chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PP1: Note: Patient 2, who is homozygous, described by Salem et al. (PMID: 22158424) had 2 affected siblings who were also homozygous, but all 3 patients in this family also had the insertion of 3 Alu elements into intron 7, which is predicted to disrupt intronic splicing regulatory elements, resulting in the deletion of exons 1-7 observed on transcript analysis. Because of the complication of the Alu insertion, this family was not scored for PM3, PP1, or PP4.