NM_000070.3(CAPN3):c.2381-2A>G AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000201091.3

Allele description [Variation Report for NM_000070.3(CAPN3):c.2381-2A>G]

NM_000070.3(CAPN3):c.2381-2A>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.2381-2A>G

HGVS:

NC_000015.10:g.42411285A>G
NG_008660.1:g.68183A>G
NM_000070.3:c.2381-2A>GMANE SELECT
NM_024344.2:c.2363-2A>G
NM_173087.2:c.2105-2A>G
NM_173088.2:c.845-2A>G
NM_173089.2:c.386-2A>G
NM_173090.2:c.386-2A>G
LRG_849t1:c.2381-2A>G
LRG_849:g.68183A>G
NC_000015.9:g.42703483A>G
NM_000070.2:c.2381-2A>G

Links:

dbSNP: rs863224962

NCBI 1000 Genomes Browser:

rs863224962

Molecular consequence:

NM_000070.3:c.2381-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_024344.2:c.2363-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173087.2:c.2105-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173088.2:c.845-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173089.2:c.386-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_173090.2:c.386-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000255663	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 28, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22926650, 26467025
SCV000800062	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 21, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003442833	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 10330340, 15689361, 22926650, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255663

Athena Diagnostics Inc

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(May 28, 2015)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000800062

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(May 21, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV003442833

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 16, 2023)

germline

clinical testing

PubMed (5)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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

See all PubMed Citations (6)

Details of each submission

From Athena Diagnostics Inc, SCV000255663.2

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

#	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 Counsyl, SCV000800062.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003442833.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 22 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). Disruption of this splice site has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 22926650). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 217155).

#	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: Feb 20, 2024

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