NM_000070.3(CAPN3):c.1524+1G>A AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 21, 2020
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:: RCV000644980.5

Allele description [Variation Report for NM_000070.3(CAPN3):c.1524+1G>A]

NM_000070.3(CAPN3):c.1524+1G>A

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.1524+1G>A

HGVS:

NC_000015.10:g.42401811G>A
NG_008660.1:g.58709G>A
NM_000070.3:c.1524+1G>AMANE SELECT
NM_024344.2:c.1524+1G>A
NM_173087.2:c.1380+1G>A
LRG_849t1:c.1524+1G>A
LRG_849:g.58709G>A
NC_000015.9:g.42694009G>A
NM_000070.2:c.1524+1G>A

Links:

dbSNP: rs1275289254

NCBI 1000 Genomes Browser:

rs1275289254

Molecular consequence:

NM_000070.3:c.1524+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_024344.2:c.1524+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_173087.2:c.1380+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000766710	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 21, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16199547, 10330340, 15689361, 17258832, 19556129, 20635405, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000766710

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 21, 2020)

germline

clinical testing

PubMed (7)
[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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000766710.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). Experimental studies have shown that alteration of this splice site disrupts mRNA splicing (PMID: 20635405). Disruption of this splice site has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy and Emery-Dreifuss muscular dystrophy (PMID: 17258832, 19556129, 20635405). ClinVar contains an entry for this variant (Variation ID: 536512). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the CAPN3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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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