NM_000070.3(CAPN3):c.2257G>A (p.Asp753Asn) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Mar 26, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000410341.22

Allele description [Variation Report for NM_000070.3(CAPN3):c.2257G>A (p.Asp753Asn)]

NM_000070.3(CAPN3):c.2257G>A (p.Asp753Asn)

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.2257G>A (p.Asp753Asn)

Other names:

p.Asp753Asn

HGVS:

NC_000015.10:g.42410660G>A
NG_008660.1:g.67558G>A
NM_000070.3:c.2257G>AMANE SELECT
NM_024344.2:c.2239G>A
NM_173087.2:c.1981G>A
NM_173088.2:c.721G>A
NM_173089.2:c.262G>A
NM_173090.2:c.262G>A
NP_000061.1:p.Asp753Asn
NP_077320.1:p.Asp747Asn
NP_775110.1:p.Asp661Asn
NP_775111.1:p.Asp241Asn
NP_775112.1:p.Asp88Asn
NP_775113.1:p.Asp88Asn
LRG_849t1:c.2257G>A
LRG_849:g.67558G>A
LRG_849p1:p.Asp753Asn
NC_000015.9:g.42702858G>A
NM_000070.2:c.2257G>A

Protein change:

D241N

Links:

dbSNP: rs146923842

NCBI 1000 Genomes Browser:

rs146923842

Molecular consequence:

NM_000070.3:c.2257G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.2239G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1981G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173089.2:c.262G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_173090.2:c.262G>A - 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
SCV000645492	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16141003, 18854869, 28492532
SCV000915670	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Jan 9, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17318636, 18854869, 15689361, 16141003, 15221789 Citation Link,
SCV001193895	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Uncertain significance (Dec 17, 2019)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17318636, 17994539, 17897828, 18854869, 20044116, 16141003, 27884173, 30564623 Citation Link,
SCV001456374	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV001737224	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004807008	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene.

Sáenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D, Camaño P, Urtasun M, Vílchez J, Gutiérrez-Rivas E, Emparanza J, Merlini L, Paisán C, Goicoechea M, Blázquez L, Eymard B, Lochmuller H, Walter M, Bonnemann C, Figarella-Branger D, Kaplan JC, Urtizberea JA, et al.

Brain. 2005 Apr;128(Pt 4):732-42. Epub 2005 Feb 2.

PubMed [citation]

PMID:: 15689361

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645492.6

#	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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 753 of the CAPN3 protein (p.Asp753Asn). This variant is present in population databases (rs146923842, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with limb girdle muscular dystrophy (PMID: 16141003, 18854869). ClinVar contains an entry for this variant (Variation ID: 281081). 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. 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

From Illumina Laboratory Services, Illumina, SCV000915670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Across a selection of the available literature, the CAPN3 c.2257G>A (p.Arg753Asn) is identified in six probands described to have limb girdle muscular dystrophy in a heterozygous state and five probands in a compound heterozygous state (Fanin et al. 2004; Piluso et al. 2005; Saenz et al. 2005; Todorova et al. 2007; Fanin et al. 2009). The p.Arg753Asn variant absent from at least 400 controls and is reported at a frequency of 0.00118 in the European (non-Finnish) population of the Exome Aggregation Consortium. Todorova et al. (2007) noted that the variant, when observed in a heterozygous state in probands with limb girdle muscular dystrophy, seemed to confer a later onset and milder phenotype. Based on the evidence, the p.Asp753Asn variant is classified as likely pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Myriad Genetics, Inc., SCV001193895.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

NM_000070.2(CAPN3):c.2257G>A(D753N) is classified as a variant of uncertain significance in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636, 17994539, 17897828, 18854869, 20044116, 16141003, 27884173 and 30564623. Classification of NM_000070.2(CAPN3):c.2257G>A(D753N) is based on the following criteria: At this time, there is insufficient or conflicting evidence to classify this variant as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001456374.1

#	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

From Genome-Nilou Lab, SCV001737224.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807008.1

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

#	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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