rs1555423217

Variant names:

• chr15-42410982-AG-TCATCT
• rs1555423217
• NM_000070.3:c.2362_2363delAGinsTCATCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1 PM2_Supporting PP4_Strong PM3_Strong PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 23/24 that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been detected in at least 30 individuals with limb girdle muscular dystrophy, including in a homozygous state in one patient (0.5 pts, PMID:18337726), in trans with a pathogenic variant in at least one patient (c.643_663del p.(Ser215_Gly221del), 1.0 pt, PMID:9150160), and in unknown phase with a pathogenic variant (c.223dup p.(Tyr75LeufsTer5), 0.5 pts, PMID:30564623, LOVD Individual #00220184) (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:18337726). The variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID:9150160). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127307/MONDO:0015152/187

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:1
• Conservation: PhyloP100: 5.91

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2362_2363delAGinsTCATCT	p.Arg788SerfsTer14	frameshift_variant, missense_variant	Exon 22 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2362_2363delAGinsTCATCT	p.Arg788SerfsTer14	frameshift_variant, missense_variant	Exon 22 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.367_368delAGinsTCATCT	p.Arg123SerfsTer14	frameshift_variant, missense_variant	Exon 9 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.367_368delAGinsTCATCT	p.Arg123SerfsTer14	frameshift_variant, missense_variant	Exon 9 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.367_368delAGinsTCATCT	p.Arg123SerfsTer14	frameshift_variant, missense_variant	Exon 10 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.367_368delAGinsTCATCT	p.Arg123SerfsTer14	frameshift_variant, missense_variant	Exon 9 of 11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.265_266delAGinsTCATCT	p.Arg89SerfsTer14	frameshift_variant, missense_variant	Exon 9 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2798_*2799delAGinsTCATCT		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2798_*2799delAGinsTCATCT		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Dec 02, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 34 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18337726, 10330340, 22194990, 16607617, 18055493, 15757244, 28615891, 9150160, 25900067, 9762961, 12461690, 17236769, 7720071, 16344536, 18563459, 21984748, 28103310, 31011535, 30919934, 31127727, 35741838, 15689361, 30564623) -

Jun 18, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. -

Apr 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3 Other:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg788Serfs*14) in the CAPN3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the CAPN3 protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 18563459, 21984748, 22194990). This variant is also known as 2362AG->TCATCT. ClinVar contains an entry for this variant (Variation ID: 17618). For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 19, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Guipuzcoa province in the Basque country of Spain, and in Brazil, [Urtasun et al 1998, de Paula et al 2002]. -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

Jan 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CAPN3 c.2362_2363delinsTCATCT (p.Arg788SerfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251342 control chromosomes (gnomAD). c.2362_2363delinsTCATCT has been reported in the literature in several homozygous- and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Richard_1997, de Paula_2002, Saenz_2005), where muscle biopsy samples derived from multiple homozygote patients demonstrated complete- or partial loss of calpain (see e.g. de Paula_2002, Saenz_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000070.3: c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 23/24 that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been detected in at least 30 individuals with limb girdle muscular dystrophy, including in a homozygous state in one patient (0.5 pts, PMID: 18337726), in trans with a pathogenic variant in at least one patient (c.643_663del p.(Ser215_Gly221del), 1.0 pt, PMID: 9150160), and in unknown phase with a pathogenic variant (c.223dup p.(Tyr75LeufsTer5), 0.5 pts, PMID: 30564623, LOVD Individual #00220184) (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: 18337726). The variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID: 9150160). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myositis, eosinophilic Pathogenic:1

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555423217; hg19: chr15-42703180;