15-42399548-C-T

Variant names:

• chr15-42399548-C-T
• rs200646556
• NM_000070.3:c.1250C>T

Variant summary

Our verdict is Pathogenic. The variant received 5 ACMG points: 5P and 0B. PP4_Moderate PP3 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1250C>T variant in CAPN3 is a missense variant predicted to cause the substitution of threonine by methionine at codon 417, p.(Thr417Met). Across a selection of the available literature, this variant has been detected in at least seven individuals with features consistent with LGMD (PMID:19556129, 27447704, 16650086, 37526466), including in a homozygous state in two patients without reported familial consanguinity (1.0 pt, PMID:37526466) and confirmed in trans with a pathogenic variant in at least three patients (c.550del p.(Thr184ArgfsTer36) x2, 2.0 pts, PMID:27447704, 37526466; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 1.0 pt, PMID:16650086) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID:16650086; PP4_Moderate). The filtering allele frequency of this variant is 0.0001353 (the upper threshold of the 95% CI of 130/1111468 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.90, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). A minigene assay showed the variant does not affect splicing (PMID:32668095), consistent with the SpliceAI score of 0.02. In vitro evidence indicates that the p.Thr417Met amino acid change results in accelerated autoproteolysis, rendering the enzyme inactive prematurely (PMID:19226146). 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; 05/03/2025): PM3_Very Strong, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511300/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 7.91
• Publications: 10 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 5 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.1250C>T	p.Thr417Met	missense	Exon 10 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.1250C>T	p.Thr417Met	missense	Exon 10 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1106C>T	p.Thr369Met	missense	Exon 9 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.1250C>T	p.Thr417Met	missense	Exon 10 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1250C>T	p.Thr417Met	missense	Exon 10 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1106C>T	p.Thr369Met	missense	Exon 9 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251420 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461282 Hom.: 0 Cov.: 30 AF XY: 0.0000949 AC XY: 69 AN XY: 727004

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111468

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74308

African (AFR) AF: 0.0000483 AC: 2 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:6

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 417 of the CAPN3 protein (p.Thr417Met). This variant is present in population databases (rs200646556, gnomAD 0.008%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 20517216, 25079074, 25135358). ClinVar contains an entry for this variant (Variation ID: 281505). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic.

Feb 05, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19226146). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.90 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000281505 /PMID: 15689361). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25135358). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 01, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 09, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5_strong,PP3_strong,PM2,PP2_supporting?

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Thr417Met variant in CAPN3 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) Trio exome analysis showed this variant to be de novo. The p.Thr417Met variant in CAPN3 has been reported in 4 individuals (including 1 French, 1 European Canadian individual) with LGMD (PMID: 25135358, 25079074,16650086), and has been identified in 0.008324% (2/24026) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200646556). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Animal models in rats have shown that this variant impacts calcium binding for the protein and causes LGMD (PMID: 19226146). The presence of this variant in combination with 2 reported pathogenic variants, p.Thr184Argfs and p.Glu622Argfs, and in 2 individuals with LGMD increases the likelihood that the p.Thr417Met variant is pathogenic (Variation ID: 17621, 290296). This variant has also been reported pathogenic in ClinVar (Variation ID: 281505). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant, functional evidence, and multiple occurrences with pathogenic CAPN3 variants in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PS2, PP3, PM3_Strong, PS3_Moderate (Richards 2015).

not provided Pathogenic:6

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CAPN3: PM3:Very Strong, PM2, PP3, PS3:Supporting

Apr 30, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PS4_moderate, PP3, PP4

Jun 02, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in apparent homozygous state in patients with LGMD in the literature and not observed in homozygous state in controls (PMID: 25135358, 25214167); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25135358, 19226146, 15689361, 19556129, 25214167, 25079074, 16650086, 32703463, 29792937, 31788660, 32528171, 32668095, Koken_2022_Abstract, 34440373, 34493867)

Mar 17, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:3

Jun 27, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 03, 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.1250C>T variant in CAPN3 is a missense variant predicted to cause the substitution of threonine by methionine at codon 417, p.(Thr417Met). Across a selection of the available literature, this variant has been detected in at least seven individuals with features consistent with LGMD (PMID: 19556129, 27447704, 16650086, 37526466), including in a homozygous state in two patients without reported familial consanguinity (1.0 pt, PMID: 37526466) and confirmed in trans with a pathogenic variant in at least three patients (c.550del p.(Thr184ArgfsTer36) x2, 2.0 pts, PMID: 27447704, 37526466; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 1.0 pt, PMID: 16650086) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 16650086; PP4_Moderate). The filtering allele frequency of this variant is 0.0001353 (the upper threshold of the 95% CI of 130/1111468 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.90, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). A minigene assay showed the variant does not affect splicing (PMID: 32668095), consistent with the SpliceAI score of 0.02. In vitro evidence indicates that the p.Thr417Met amino acid change results in accelerated autoproteolysis, rendering the enzyme inactive prematurely (PMID: 19226146). 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; 05/03/2025): PM3_Very Strong, PP4_Moderate, PP3.

Dec 02, 2022

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.1250C>T (p.Thr417Met) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.2e-05 vs 0.0032), allowing no conclusion about variant significance. c.1250C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 15689361, 18258189, 25135358, 27447704, 34440373, 25079074, 16650086). 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Mar 21, 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

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.97
MPC		0.64
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.84
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200646556; hg19: chr15-42691746; COSMIC: COSV58826190; COSMIC: COSV58826190;