NM_000070.3(CAPN3):c.1715G>C (p.Arg572Pro) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 3, 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:: RCV003517174.2

Allele description [Variation Report for NM_000070.3(CAPN3):c.1715G>C (p.Arg572Pro)]

NM_000070.3(CAPN3):c.1715G>C (p.Arg572Pro)

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.1715G>C (p.Arg572Pro)

HGVS:

NC_000015.10:g.42402972G>C
NG_008660.1:g.59870G>C
NM_000070.3:c.1715G>CMANE SELECT
NM_024344.2:c.1715G>C
NM_173087.2:c.1571G>C
NM_173088.2:c.179G>C
NP_000061.1:p.Arg572Pro
NP_077320.1:p.Arg572Pro
NP_775110.1:p.Arg524Pro
NP_775111.1:p.Arg60Pro
LRG_849t1:c.1715G>C
LRG_849:g.59870G>C
LRG_849p1:p.Arg572Pro
NC_000015.9:g.42695170G>C
NM_000070.2:c.1715G>C

Protein change:

R524P

Links:

dbSNP: rs121434544

NCBI 1000 Genomes Browser:

rs121434544

Molecular consequence:

NM_000070.3:c.1715G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1715G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1571G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.179G>C - 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
SCV004267145	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16141003, 32557990, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004267145

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 3, 2023)

germline

clinical testing

PubMed (3)
[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

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

A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity.

Vissing J, Dahlqvist JR, Roudaut C, Poupiot J, Richard I, Duno M, Krag T.

Hum Mutat. 2020 Sep;41(9):1507-1513. doi: 10.1002/humu.24066. Epub 2020 Jul 11.

PubMed [citation]

PMID:: 32557990

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004267145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 287131). 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. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 32557990). 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 individual(s) with autosomal dominant limb-girdle muscular dystrophy (PMID: 16141003, 32557990). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 572 of the CAPN3 protein (p.Arg572Pro).

#	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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