NM_000070.3(CAPN3):c.2138A>C (p.Asn713Thr) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 19, 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:: RCV003631113.2

Allele description [Variation Report for NM_000070.3(CAPN3):c.2138A>C (p.Asn713Thr)]

NM_000070.3(CAPN3):c.2138A>C (p.Asn713Thr)

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.2138A>C (p.Asn713Thr)

HGVS:

NC_000015.10:g.42410450A>C
NG_008660.1:g.67348A>C
NM_000070.3:c.2138A>CMANE SELECT
NM_024344.2:c.2120A>C
NM_173087.2:c.1862A>C
NM_173088.2:c.602A>C
NM_173089.2:c.143A>C
NM_173090.2:c.143A>C
NP_000061.1:p.Asn713Thr
NP_077320.1:p.Asn707Thr
NP_775110.1:p.Asn621Thr
NP_775111.1:p.Asn201Thr
NP_775112.1:p.Asn48Thr
NP_775113.1:p.Asn48Thr
LRG_849t1:c.2138A>C
LRG_849:g.67348A>C
LRG_849p1:p.Asn713Thr
NC_000015.9:g.42702648A>C

Protein change:

N201T

Links:

dbSNP: rs886044264

NCBI 1000 Genomes Browser:

rs886044264

Molecular consequence:

NM_000070.3:c.2138A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.2120A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1862A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.602A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173089.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_173090.2:c.143A>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
SCV004509332	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30564623, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004509332

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 19, 2023)

germline

clinical testing

PubMed (2)
[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

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

PMID:: 30564623
PMCID:: PMC6292381

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, SCV004509332.1

#	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 asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 713 of the CAPN3 protein (p.Asn713Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 289785). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. 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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