NM_000070.3(CAPN3):c.1355A>G (p.Asp452Gly) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 3, 2022
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:: RCV003070852.2

Allele description [Variation Report for NM_000070.3(CAPN3):c.1355A>G (p.Asp452Gly)]

NM_000070.3(CAPN3):c.1355A>G (p.Asp452Gly)

Genes:

LOC130056921:ATAC-STARR-seq lymphoblastoid active region 9300 [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.1355A>G (p.Asp452Gly)

HGVS:

NC_000015.10:g.42401641A>G
NG_008660.1:g.58539A>G
NM_000070.2:c.1355A>G
NM_000070.3:c.1355A>GMANE SELECT
NM_024344.2:c.1355A>G
NM_173087.2:c.1211A>G
NM_212464.2:c.1094A>G
NM_212467.2:c.*1048A>G
NP_000061.1:p.Asp452Gly
NP_077320.1:p.Asp452Gly
NP_775110.1:p.Asp404Gly
NP_997629.1:p.Asp365Gly
LRG_849t1:c.1355A>G
LRG_849:g.58539A>G
LRG_849p1:p.Asp452Gly
NC_000015.9:g.42693839A>G

Protein change:

D365G

Molecular consequence:

NM_000070.3:c.1355A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1355A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1211A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_212464.2:c.1094A>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
SCV003445636	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003445636

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 3, 2022)

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	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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003445636.1

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 452 of the CAPN3 protein (p.Asp452Gly). This variant is present in population databases (rs549092966, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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