NM_000070.3(CAPN3):c.1357dup (p.Thr453fs) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 31, 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:: RCV002690317.5

Allele description [Variation Report for NM_000070.3(CAPN3):c.1357dup (p.Thr453fs)]

NM_000070.3(CAPN3):c.1357dup (p.Thr453fs)

Genes:

LOC130056921:ATAC-STARR-seq lymphoblastoid active region 9300 [Gene]
CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.1357dup (p.Thr453fs)

HGVS:

NC_000015.10:g.42401643dup
NG_008660.1:g.58541dup
NM_000070.3:c.1357dupMANE SELECT
NM_024344.2:c.1357dup
NM_173087.2:c.1213dup
NM_212464.2:c.1096dup
NM_212467.2:c.*1050dup
NP_000061.1:p.Thr453fs
NP_077320.1:p.Thr453fs
NP_775110.1:p.Thr405fs
NP_997629.1:p.Thr366Asnfs
LRG_849t1:c.1357dup
LRG_849:g.58541dup
LRG_849p1:p.Thr453fs
NC_000015.9:g.42693840_42693841insA
NC_000015.9:g.42693841dup

Protein change:

T405fs

Molecular consequence:

NM_000070.3:c.1357dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024344.2:c.1357dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173087.2:c.1213dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_212464.2:c.1096dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV002994941	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 28, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32528171, 10330340, 15689361, 28492532
SCV004031062	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 31, 2023)	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002994941

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 28, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004031062

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 31, 2023)

biparental

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	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

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

Töpf A, Johnson K, Bates A, Phillips L, Chao KR, England EM, Laricchia KM, Mullen T, Valkanas E, Xu L, Bertoli M, Blain A, Casasús AB, Duff J, Mroczek M, Specht S, Lek M, Ensini M, MacArthur DG; MYO-SEQ consortium., Straub V.

Genet Med. 2020 Sep;22(9):1478-1488. doi: 10.1038/s41436-020-0840-3. Epub 2020 Jun 11.

PubMed [citation]

PMID:: 32528171
PMCID:: PMC7462745

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 (5)

Details of each submission

From Invitae, SCV002994941.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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 create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with CAPN3-related conditions (PMID: 32528171). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr453Asnfs*18) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361).

#	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 Intergen, Intergen Genetics and Rare Diseases Diagnosis Center, SCV004031062.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	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	biparental	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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