rs863224958

Positions:

• chr15-42359951-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_Strong PP4_Strong PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.146G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 49 (p.Arg49His). This variant has been detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID:16650086, 17318636, 25135358; ClinVar SCV003459936.1 internal data communication, ClinVar SCV001164521.1 internal data communication), including in a homozygous state in one individual (ClinVar SCV001164521.1 internal data communication, 0.5 pts), confirmed in trans with a pathogenic variant (c.967G>T p.(Glu323Ter), 1.0 pt, PMID:17318636), and confirmed in trans with two variants not yet curated by the VCEP and considered VUS (0.5 pts) (PM3_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:16650086). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (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; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347493/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 8.35

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 10 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.146G>A	p.Arg49His	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.146G>A	p.Arg49His	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.146G>A	p.Arg49His	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.146G>A	p.Arg49His	missense_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5498G>A		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 20, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg49His variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg49His variant in CAPN3 has been reported in the compound heterozygous state in 5 individuals with LGMD (PMID: 17318636, 16650086, 16100770, 16411092). The presence of this variant in combination with multiple CAPN3 variants (1 reported pathogenic, 2 reported VUS, and 2 loss of function variants not reported in ClinVar) and in 5 individuals with LGMD increases the likelihood that the p.Arg49His variant is pathogenic. Another missense variant at the same position, p.Arg49Cys, has been reported likely pathogenic in ClinVar (Variation ID: 193037). This raises the possibility that a change at this position would not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong, PM4_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 217151). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the CAPN3 protein (p.Arg49His). -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2023	Variant summary: CAPN3 c.146G>A (p.Arg49His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes (gnomAD). c.146G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Krahn_2007, Monies-2016, Saat_2021, and Ozyilmaz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35157181, 27671536, 33963534, 16650086). Seven submitters have cited 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. -
Pathogenic, reviewed by expert panel	curation	ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	Jan 09, 2025	The NM_000070.3: c.146G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 49 (p.Arg49His). This variant has been detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; ClinVar SCV003459936.1 internal data communication, ClinVar SCV001164521.1 internal data communication), including in a homozygous state in one individual (ClinVar SCV001164521.1 internal data communication, 0.5 pts), confirmed in trans with a pathogenic variant (c.967G>T p.(Glu323Ter), 1.0 pt, PMID: 17318636), and confirmed in trans with two variants not yet curated by the VCEP and considered VUS (0.5 pts) (PM3_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: 16650086). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (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; 01/09/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 22, 2024	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) CAPN3 protein was found to be absent or significantly reduced in samples taken from multiple individuals carrying this variant (PMID: 16650086,19364062). 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. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2023

- -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.048	T;.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.90	.;L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.032	D;D;T;D
Polyphen		1.0	.;D;D;D
Vest4		0.90
MutPred		0.83		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.98
MPC		0.70
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs863224958; hg19: chr15-42652149; COSMIC: COSV58819321; COSMIC: COSV58819321;