NM_000070.3(CAPN3):c.1553A>G (p.Gln518Arg) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 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:: RCV001241846.7

Allele description [Variation Report for NM_000070.3(CAPN3):c.1553A>G (p.Gln518Arg)]

NM_000070.3(CAPN3):c.1553A>G (p.Gln518Arg)

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.1553A>G (p.Gln518Arg)

HGVS:

NC_000015.10:g.42402810A>G
NG_008660.1:g.59708A>G
NM_000070.3:c.1553A>GMANE SELECT
NM_024344.2:c.1553A>G
NM_173087.2:c.1409A>G
NM_173088.2:c.17A>G
NP_000061.1:p.Gln518Arg
NP_077320.1:p.Gln518Arg
NP_775110.1:p.Gln470Arg
NP_775111.1:p.Gln6Arg
LRG_849t1:c.1553A>G
LRG_849:g.59708A>G
LRG_849p1:p.Gln518Arg
NC_000015.9:g.42695008A>G
NM_000070.2:c.1553A>G

Protein change:

Q470R

Links:

dbSNP: rs764593698

NCBI 1000 Genomes Browser:

rs764593698

Molecular consequence:

NM_000070.3:c.1553A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1553A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1409A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.17A>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
SCV001414895	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19556129, 28492532
SCV002085524	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 14, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001414895

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 6, 2023)

germline

clinical testing

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

SCV002085524

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Feb 14, 2020)

germline

clinical testing

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

Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A.

Charlton R, Henderson M, Richards J, Hudson J, Straub V, Bushby K, Barresi R.

Neuromuscul Disord. 2009 Jul;19(7):449-57. doi: 10.1016/j.nmd.2009.05.005. Epub 2009 Jun 24.

PubMed [citation]

PMID:: 19556129

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001414895.4

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

Description

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 518 of the CAPN3 protein (p.Gln518Arg). This variant is present in population databases (rs764593698, gnomAD 0.006%). 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. 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 not expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 967031). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) (PMID: 19556129).

#	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

From Natera, Inc., SCV002085524.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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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