NM_000070.3(CAPN3):c.2069_2070del (p.His690fs) AND Autosomal recessive limb-girdle muscular dystrophy type 2A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 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:: RCV000667099.7

Allele description [Variation Report for NM_000070.3(CAPN3):c.2069_2070del (p.His690fs)]

NM_000070.3(CAPN3):c.2069_2070del (p.His690fs)

Gene:

CAPN3:calpain 3 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

15q15.1

Genomic location:

Preferred name:

NM_000070.3(CAPN3):c.2069_2070del (p.His690fs)

HGVS:

NC_000015.10:g.42409945AC[2]
NG_008660.1:g.66843AC[2]
NM_000070.3:c.2069_2070delMANE SELECT
NM_024344.2:c.2051_2052del
NM_173087.2:c.1793_1794del
NM_173088.2:c.533_534del
NM_173089.2:c.74_75del
NM_173090.2:c.74_75del
NP_000061.1:p.His690fs
NP_077320.1:p.His684fs
NP_775110.1:p.His598fs
NP_775111.1:p.His178fs
NP_775112.1:p.His25fs
NP_775113.1:p.His25fs
LRG_849t1:c.2069_2070del
LRG_849:g.66843AC[2]
LRG_849p1:p.His690fs
NC_000015.9:g.42702143AC[2]
NC_000015.9:g.42702143_42702144del
NM_000070.2:c.2069_2070delAC

Protein change:

H178fs

Links:

dbSNP: rs1555423046

NCBI 1000 Genomes Browser:

rs1555423046

Molecular consequence:

NM_000070.3:c.2069_2070del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024344.2:c.2051_2052del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173087.2:c.1793_1794del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173088.2:c.533_534del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173089.2:c.74_75del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173090.2:c.74_75del - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

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Taxonomy Links for Protein (Select 46015944) (1)
Taxonomy
Gene neighbors for Gene (Select 89511189) (5)
Gene
Chain G, Galactose-binding lectin
Chain G, Galactose-binding lectin
gi|46015948|pdb|1V6M|G

Protein
Chain C, Galactose-binding lectin
Chain C, Galactose-binding lectin
gi|46015944|pdb|1V6M|C

Protein
esv2759189 (1)
dbVar

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000791496	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Oct 9, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18563459, 7720071 Citation Link,
SCV002238889	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10330340, 15689361, 7720071, 21204801, 27363342, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000791496

Counsyl

criteria provided, single submitter

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

Pathogenic
(Oct 9, 2017)

unknown

clinical testing

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

Citation Link,

SCV002238889

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 16, 2023)

germline

clinical testing

PubMed (6)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of novel CAPN3 isoforms in white blood cells: an alternative approach for limb-girdle muscular dystrophy 2A diagnosis.

Blázquez L, Azpitarte M, Sáenz A, Goicoechea M, Otaegui D, Ferrer X, Illa I, Gutierrez-Rivas E, Vilchez JJ, López de Munain A.

Neurogenetics. 2008 Jul;9(3):173-82. doi: 10.1007/s10048-008-0129-1. Epub 2008 Jun 19.

PubMed [citation]

PMID:: 18563459

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 Counsyl, SCV000791496.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002238889.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.His690Argfs*9) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with inherited muscular disorders, including autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 21204801, 27363342). ClinVar contains an entry for this variant (Variation ID: 551927). For these reasons, this variant has been classified as Pathogenic.

#	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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