NM_000070.3(CAPN3):c.1699G>T (p.Gly567Trp) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 28, 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:: RCV000174442.23

Allele description [Variation Report for NM_000070.3(CAPN3):c.1699G>T (p.Gly567Trp)]

NM_000070.3(CAPN3):c.1699G>T (p.Gly567Trp)

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.1699G>T (p.Gly567Trp)

HGVS:

NC_000015.10:g.42402956G>T
NG_008660.1:g.59854G>T
NM_000070.3:c.1699G>TMANE SELECT
NM_024344.2:c.1699G>T
NM_173087.2:c.1555G>T
NM_173088.2:c.163G>T
NP_000061.1:p.Gly567Trp
NP_000061.1:p.Gly567Trp
NP_000061.1:p.Gly567Trp
NP_077320.1:p.Gly567Trp
NP_775110.1:p.Gly519Trp
NP_775111.1:p.Gly55Trp
LRG_849t1:c.1699G>T
LRG_849:g.59854G>T
LRG_849p1:p.Gly567Trp
NC_000015.9:g.42695154G>T
NM_000070.2:c.1699G>T
P20807:p.Gly567Trp

Protein change:

G519W

Links:

UniProtKB: P20807#VAR_009589; dbSNP: rs727503839

NCBI 1000 Genomes Browser:

rs727503839

Molecular consequence:

NM_000070.3:c.1699G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024344.2:c.1699G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173087.2:c.1555G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_173088.2:c.163G>T - 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
SCV000645478	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9150160, 10330340, 26404900, 28492532
SCV002085534	Natera, Inc.	no assertion criteria provided	Pathogenic (Jul 2, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645478

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 28, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002085534

Natera, Inc.

no assertion criteria provided

Pathogenic
(Jul 2, 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

Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins.

Richard I, Brenguier L, Dinçer P, Roudaut C, Bady B, Burgunder JM, Chemaly R, Garcia CA, Halaby G, Jackson CE, Kurnit DM, Lefranc G, Legum C, Loiselet J, Merlini L, Nivelon-Chevallier A, Ollagnon-Roman E, Restagno G, Topaloglu H, Beckmann JS.

Am J Hum Genet. 1997 May;60(5):1128-38.

PubMed [citation]

PMID:: 9150160
PMCID:: PMC1712426

Calpainopathy-a survey of mutations and polymorphisms.

Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, et al.

Am J Hum Genet. 1999 Jun;64(6):1524-40.

PubMed [citation]

PMID:: 10330340
PMCID:: PMC1377896

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645478.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 567 of the CAPN3 protein (p.Gly567Trp). This variant is present in population databases (rs727503839, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 9150160, 10330340, 26404900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 166791). 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 expected to disrupt CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic.

#	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., SCV002085534.1

#	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: Nov 3, 2024

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