NM_000070.3(CAPN3):c.1742C>G (p.Ser581Cys) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 6, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003518800.2

Allele description [Variation Report for NM_000070.3(CAPN3):c.1742C>G (p.Ser581Cys)]

NM_000070.3(CAPN3):c.1742C>G (p.Ser581Cys)

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.1742C>G (p.Ser581Cys)

HGVS:

NC_000015.10:g.42402999C>G
NG_008660.1:g.59897C>G
NM_000070.3:c.1742C>GMANE SELECT
NM_024344.2:c.1742C>G
NM_173087.2:c.1598C>G
NM_173088.2:c.206C>G
NM_212464.2:c.*858C>G
NM_212467.2:c.*1435C>G
NP_000061.1:p.Ser581Cys
NP_077320.1:p.Ser581Cys
NP_775110.1:p.Ser533Cys
NP_775111.1:p.Ser69Cys
LRG_849t1:c.1742C>G
LRG_849:g.59897C>G
LRG_849p1:p.Ser581Cys
NC_000015.9:g.42695197C>G

Protein change:

S533C

Molecular consequence:

NM_000070.3:c.1742C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1742C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1598C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.206C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004296938	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11525884, 17258832, 27066573, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004296938

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 6, 2023)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy.

Chae J, Minami N, Jin Y, Nakagawa M, Murayama K, Igarashi F, Nonaka I.

Neuromuscul Disord. 2001 Sep;11(6-7):547-55.

PubMed [citation]

PMID:: 11525884

Characterization of lobulated fibers in limb girdle muscular dystrophy type 2A by gene expression profiling.

Keira Y, Noguchi S, Kurokawa R, Fujita M, Minami N, Hayashi YK, Kato T, Nishino I.

Neurosci Res. 2007 Apr;57(4):513-21. Epub 2007 Jan 5.

PubMed [citation]

PMID:: 17258832

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296938.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 11525884, 17258832, 27066573). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 581 of the CAPN3 protein (p.Ser581Cys).

#	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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