NM_000070.3(CAPN3):c.801+2T>G AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 29, 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:: RCV002852310.3

Allele description [Variation Report for NM_000070.3(CAPN3):c.801+2T>G]

NM_000070.3(CAPN3):c.801+2T>G

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.801+2T>G

HGVS:

NC_000015.10:g.42389098T>G
NG_008660.1:g.45996T>G
NM_000070.3:c.801+2T>GMANE SELECT
NM_024344.2:c.801+2T>G
NM_173087.2:c.801+2T>G
LRG_849t1:c.801+2T>G
LRG_849:g.45996T>G
NC_000015.9:g.42681296T>G

Molecular consequence:

NM_000070.3:c.801+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_024344.2:c.801+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_173087.2:c.801+2T>G - 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
SCV003224532	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9452114, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003224532

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 29, 2022)

germline

clinical testing

PubMed (2)
[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

A small in-frame deletion within the protease domain of muscle-specific calpain, p94 causes early-onset limb-girdle muscular dystrophy 2A.

Häffner K, Speer A, Hübner C, Voit T, Oexle K.

Hum Mutat. 1998;Suppl 1:S298-300. No abstract available.

PubMed [citation]

PMID:: 9452114

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, SCV003224532.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 9452114). The resulting mRNA is expected to undergo nonsense-mediated decay. Disruption of this splice site has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9452114). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the CAPN3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result 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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