rs1555420634

Variant names:

• chr15-42388996-G-A
• rs1555420634
• NM_000070.3:c.701G>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.701G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 234 (p.Gly234Glu). This variant has been detected in at least 8 individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, PMID:27500519, 17994539) and in trans with a likely pathogenic or pathogenic variant in at least one patient (c.1319G>A p.(Arg440Gln), 1.0 pt, PMID:17994539) (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:17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, 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/CA16609628/MONDO:0015152/187

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.90

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 rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.701G>A	p.Gly234Glu	missense_variant	Exon 5 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.701G>A	p.Gly234Glu	missense_variant	Exon 5 of 23		NP_077320.1
CAPN3	NM_173087.2	c.701G>A	p.Gly234Glu	missense_variant	Exon 5 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.701G>A	p.Gly234Glu	missense_variant	Exon 5 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*497G>A		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*497G>A		3_prime_UTR_variant	Exon 9 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

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

Sep 24, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2023

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM1, PM2, PM5, PP3, PP5, PS3; Variant found in a heterzygous state -

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). 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: 501754). This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu). -

Dec 03, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Gly234Glu variant in CAPN3 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, 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. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015). -

not provided Pathogenic:2

Feb 23, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_SUP, PS3, PM3 -

May 11, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

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.701G>A variant in CAPN3 is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 234 (p.Gly234Glu). This variant has been detected in at least 8 individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pt, PMID: 27500519, 17994539) and in trans with a likely pathogenic or pathogenic variant in at least one patient (c.1319G>A p.(Arg440Gln), 1.0 pt, PMID: 17994539) (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: 17994539). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.86, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;H;H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.56, 0.26, 0.61	.;P;B;P
Vest4		0.98
MutPred		0.98		Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);Loss of catalytic residue at V235 (P = 0.0724);
MVP		0.98
MPC		0.43
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.98

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: rs1555420634; hg19: chr15-42681194;