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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 4, 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:: RCV003114302.10

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
Identifiers:: MONDO: MONDO:0015152; MedGen: C2931907; OMIM: PS253600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003801335	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 4, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 30564623, 31555977, 26404900, 32342993, 35309930, 9150160, 32557990 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003801335

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 4, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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

European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A).

Barp A, Laforet P, Bello L, Tasca G, Vissing J, Monforte M, Ricci E, Choumert A, Stojkovic T, Malfatti E, Pegoraro E, Semplicini C, Stramare R, Scheidegger O, Haberlova J, Straub V, Marini-Bettolo C, Løkken N, Diaz-Manera J, Urtizberea JA, Mercuri E, Kynčl M, et al.

J Neurol. 2020 Jan;267(1):45-56. doi: 10.1007/s00415-019-09539-y. Epub 2019 Sep 25.

PubMed [citation]

PMID:: 31555977

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003801335.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: CAPN3 c.1699G>T (p.Gly567Trp) results in a non-conservative amino acid change located in peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes (gnomAD). c.1699G>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with (suspected) Limb-Girdle Muscular Dystrophy (e.g., Richard_1997, Magri_2015, Nallamilli_2018, Barp_2020). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence, demonstrating the lack of calpain activity in a cell line homozygous for the variant (Cerino_2020). Five ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Nov 3, 2024

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