NM_000070.3(CAPN3):c.1621C>G (p.Arg541Gly) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 13, 2021
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:: RCV000817085.6

Allele description [Variation Report for NM_000070.3(CAPN3):c.1621C>G (p.Arg541Gly)]

NM_000070.3(CAPN3):c.1621C>G (p.Arg541Gly)

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.1621C>G (p.Arg541Gly)

HGVS:

NC_000015.10:g.42402878C>G
NG_008660.1:g.59776C>G
NM_000070.3:c.1621C>GMANE SELECT
NM_024344.2:c.1621C>G
NM_173087.2:c.1477C>G
NM_173088.2:c.85C>G
NP_000061.1:p.Arg541Gly
NP_077320.1:p.Arg541Gly
NP_775110.1:p.Arg493Gly
NP_775111.1:p.Arg29Gly
LRG_849t1:c.1621C>G
LRG_849:g.59776C>G
LRG_849p1:p.Arg541Gly
NC_000015.9:g.42695076C>G
NM_000070.2:c.1621C>G

Protein change:

R29G

Links:

dbSNP: rs142004418

NCBI 1000 Genomes Browser:

rs142004418

Molecular consequence:

NM_000070.3:c.1621C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1621C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1477C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.85C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1)
Synonyms:: LEYDEN-MOEBIUS MUSCULAR DYSTROPHY; MUSCULAR DYSTROPHY, PELVOFEMORAL; Limb-girdle muscular dystrophy, type 2A; 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
SCV000957625	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 13, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14981715, 16141003, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000957625

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 13, 2021)

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

Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia.

Canki-Klain N, Milic A, Kovac B, Trlaja A, Grgicevic D, Zurak N, Fardeau M, Leturcq F, Kaplan JC, Urtizberea JA, Politano L, Piluso G, Feingold J.

Am J Med Genet A. 2004 Mar 1;125A(2):152-6. Review.

PubMed [citation]

PMID:: 14981715

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957625.3

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

Description

This sequence change replaces arginine with glycine at codon 541 of the CAPN3 protein (p.Arg541Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of CAPN3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 282677). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg541 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 14981715, 16141003), which suggests that this may be a clinically significant amino acid residue. 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: Jan 13, 2025

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