NM_000070.3(CAPN3):c.1524G>A (p.Glu508=) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 18, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001249768.8

Allele description [Variation Report for NM_000070.3(CAPN3):c.1524G>A (p.Glu508=)]

NM_000070.3(CAPN3):c.1524G>A (p.Glu508=)

Gene:

CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.1524G>A (p.Glu508=)

HGVS:

NC_000015.10:g.42401810G>A
NG_008660.1:g.58708G>A
NM_000070.3:c.1524G>AMANE SELECT
NM_024344.2:c.1524G>A
NM_173087.2:c.1380G>A
NP_000061.1:p.Glu508=
NP_077320.1:p.Glu508=
NP_775110.1:p.Glu460=
LRG_849t1:c.1524G>A
LRG_849:g.58708G>A
LRG_849p1:p.Glu508=
NC_000015.9:g.42694008G>A
NM_000070.2:c.1524G>A

Links:

dbSNP: rs886043432

NCBI 1000 Genomes Browser:

rs886043432

Molecular consequence:

NM_000070.3:c.1524G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_024344.2:c.1524G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_173087.2:c.1380G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1)
Synonyms:: Limb-girdle muscular dystrophy, type 2A; Limb-girdle muscular dystrophy type 2; Muscular dystrophy, pelvofemoral; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009675; MedGen: C1869123; Orphanet: 267; OMIM: 253600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001423802	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Mar 24, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17236769, 17994539 Citation Link,
SCV002172393	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 18, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16141003, 17994539, 32528171, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001423802

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Likely pathogenic
(Mar 24, 2020)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002172393

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 18, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A third of LGMD2A biopsies have normal calpain 3 proteolytic activity as determined by an in vitro assay.

Milic A, Daniele N, Lochmüller H, Mora M, Comi GP, Moggio M, Noulet F, Walter MC, Morandi L, Poupiot J, Roudaut C, Bittner RE, Bartoli M, Richard I.

Neuromuscul Disord. 2007 Feb;17(2):148-56. Epub 2007 Jan 22.

PubMed [citation]

PMID:: 17236769

Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes.

Piluso G, Politano L, Aurino S, Fanin M, Ricci E, Ventriglia VM, Belsito A, Totaro A, Saccone V, Topaloglu H, Nascimbeni AC, Fulizio L, Broccolini A, Canki-Klain N, Comi LI, Nigro G, Angelini C, Nigro V.

J Med Genet. 2005 Sep;42(9):686-93.

PubMed [citation]

PMID:: 16141003
PMCID:: PMC1736133

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001423802.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The CAPN3 c.1524G>A (p.Glu508Glu) is a synonymous splice region variant. The p.Glu508Glu variant has been reported in two studies in which it was identified in at least two individuals affected with limb girdle muscular dystrophy, in one in a homozygous state and in the other in a compound heterozygous state. In both patients, immunohistochemistry of tissue from muscle biopsy showed either neglible or absent Calpain-3 protein levels compared to normal controls (Guglieri et al. 2008). In addition, Milic et al. (2007), demonstrated that protein extracted from the muscle biopsy of a patient who carriend the p.Glu508Glu variant in a compound heterozygous state, did not have any Calpain-3 protein activity. The p.Glu508Glu variant is not found in the Genome Aggregation Database, in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Glu508Glu variant is classified as likely pathogenic for calpainopathy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002172393.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects codon 508 of the CAPN3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CAPN3 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with limb-girdle muscle weakness and/or limb-girdle muscular dystrophy (PMID: 16141003, 17994539, 32528171). ClinVar contains an entry for this variant (Variation ID: 286592). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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