NM_000070.3(CAPN3):c.550del (p.Thr184fs) AND CAPN3-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 5, 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:: RCV001849271.7

Allele description [Variation Report for NM_000070.3(CAPN3):c.550del (p.Thr184fs)]

NM_000070.3(CAPN3):c.550del (p.Thr184fs)

Gene:

CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.550del (p.Thr184fs)

Other names:

NM_000070.2:c.550del;p.Thr184Argfs*36

HGVS:

NC_000015.10:g.42387804del
NG_008660.1:g.44702del
NM_000070.3:c.550delMANE SELECT
NM_000070.3:c.550delA
NM_024344.2:c.550del
NM_173087.2:c.550del
NP_000061.1:p.Thr184fs
NP_077320.1:p.Thr184fs
NP_077320.1:p.Thr184fs
NP_775110.1:p.Thr184fs
LRG_849t1:c.550del
LRG_849:g.44702del
LRG_849p1:p.Thr184fs
NC_000015.9:g.42680001del
NC_000015.9:g.42680002del
NM_000070.2:c.550delA
NM_000070.3:c.549delAMANE SELECT
NM_000070.3:c.550del
NM_000070.3:c.550delAMANE SELECT
NM_024344.1:c.550del
p.Thr184Argfs*36
p.Thr184ArgfsTer36

Protein change:

T184fs

Links:

Genetic Testing Registry (GTR): GTR000330880; OMIM: 114240.0009; dbSNP: rs80338800

NCBI 1000 Genomes Browser:

rs80338800

Molecular consequence:

NM_000070.3:c.550del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024344.2:c.550del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173087.2:c.550del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: CAPN3-related disorder
Synonyms:: CAPN3-Related Disorders; CAPN3-related condition
Identifiers:: MedGen: CN239245

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002107142	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 15221789, 20635405, 14578192, 7720071, 21984748, 17318636, 10679950, 14981715, 16100770, 21204801, 15689361, 9266733, 15725583, 26404900, 25741868
SCV005361536	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Apr 19, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002107142

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 5, 2022)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV005361536

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Apr 19, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Molecular diagnosis in LGMD2A: mutation analysis or protein testing?

Fanin M, Fulizio L, Nascimbeni AC, Spinazzi M, Piluso G, Ventriglia VM, Ruzza G, Siciliano G, Trevisan CP, Politano L, Nigro V, Angelini C.

Hum Mutat. 2004 Jul;24(1):52-62.

PubMed [citation]

PMID:: 15221789

Transcriptional and translational effects of intronic CAPN3 gene mutations.

Nascimbeni AC, Fanin M, Tasca E, Angelini C.

Hum Mutat. 2010 Sep;31(9):E1658-69. doi: 10.1002/humu.21320.

PubMed [citation]

PMID:: 20635405
PMCID:: PMC2966865

See all PubMed Citations (15)

Details of each submission

From DASA, SCV002107142.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (15)

Description

The c.550delA;p.(Thr184Argfs*36) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15221789; 15725583; 20635405) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17621; PMID: 14578192; PMID: 7720071; PMID: 21984748; PMID: 17318636; PMID: 10679950; PMID: 14981715; PMID: 16100770; PMID: 21204801; PMID: 15689361; PMID: 9266733; PMID: 15725583) - PS4. The variant is present at low allele frequencies population databases (rs80338800 – gnomAD 0.001971%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr184Argfs*36) was detected in trans with a pathogenic variant (PMID: 26404900) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV005361536.1

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

Description

The CAPN3 c.550delA variant is predicted to result in a frameshift and premature protein termination (p.Thr184Argfs*36). This variant is one of the most common, well documented pathogenic variants to be causative for limb girdle muscular dystrophy (Fanin et al. 2003. PubMed ID: 14578192; Richard et al. 1999. PubMed ID: 10330340). This variant is reported in 0.045% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CAPN3 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive CAPN3-related disorders.

#	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 30, 2024

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