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NM_000070.3(CAPN3):c.1746-20C>G

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(1);Likely benign(1);Pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Jul 4, 2021)
Last evaluated:
Dec 4, 2020
Accession:
VCV000092408.11
Variation ID:
92408
Description:
single nucleotide variant
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NM_000070.3(CAPN3):c.1746-20C>G

Allele ID
98319
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q15.1
Genomic location
15: 42403721 (GRCh38) GRCh38 UCSC
15: 42695919 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000015.10:g.42403721C>G
NC_000015.9:g.42695919C>G
NM_000070.3:c.1746-20C>G MANE Select
... more HGVS
Protein change
-
Other names
-
Canonical SPDI
NC_000015.10:42403720:C:G
Functional consequence
-
Global minor allele frequency (GMAF)
0.00040 (G)

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00315
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00309
The Genome Aggregation Database (gnomAD) 0.00548
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00269
Trans-Omics for Precision Medicine (TOPMed) 0.00233
Links
ClinGen: CA220343
dbSNP: rs201892814
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Aug 1, 2018 RCV000585323.4
Pathogenic 1 criteria provided, single submitter Jan 1, 2017 RCV000626578.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Oct 12, 2017 RCV000078089.5
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Dec 4, 2020 RCV000559180.7
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CAPN3 - - GRCh38
GRCh37
988 1000

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Oct 12, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
GeneDx
Accession: SCV000568286.3
Submitted: (Nov 28, 2017)
Evidence details
Comment:
A variant of uncertain significance has been identified in the CAPN3 gene. The c.1746-20 C>G variant has been reported multiple times in association with LGMD2A … (more)
Pathogenic
(Jan 01, 2017)
criteria provided, single submitter
Method: clinical testing
Absent muscle fiber calpain-3
Difficulty walking
EMG: neuropathic changes
Elevated serum creatine phosphokinase
Migraine
Paresthesia
Positive Romberg sign
Progressive spinal muscular atrophy
Allele origin: unknown
Centre for Mendelian Genomics,University Medical Centre Ljubljana
Accession: SCV000747279.1
Submitted: (Dec 08, 2017)
Evidence details
Uncertain significance
(Dec 18, 2017)
criteria provided, single submitter
Method: clinical testing
Limb-girdle muscular dystrophy, type 2A
Allele origin: unknown
Counsyl
Accession: SCV000796481.1
Submitted: (Jul 10, 2018)
Evidence details
Publications
PubMed (9)
Likely benign
(Nov 23, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000109927.8
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Benign
(Dec 04, 2020)
criteria provided, single submitter
Method: clinical testing
Limb-girdle muscular dystrophy, type 2A
Allele origin: germline
Invitae
Accession: SCV000645480.6
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Aug 01, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV000692807.9
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Apr 17, 2020)
no assertion criteria provided
Method: clinical testing
Limb-girdle muscular dystrophy type 2A
Allele origin: germline
Natera, Inc.
Accession: SCV001460840.1
Submitted: (Dec 28, 2020)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. Reddy HM Journal of human genetics 2017 PMID: 27708273
Neuromuscular Pathology Case. Avila JD Journal of clinical neuromuscular disease 2015 PMID: 26301378
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. Stehlíková K BMC neurology 2014 PMID: 25135358
Eosinophils in hereditary and inflammatory myopathies. Schröder T Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 2013 PMID: 24803842
Transcriptional and translational effects of intronic CAPN3 gene mutations. Nascimbeni AC Human mutation 2010 PMID: 20635405
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. Groen EJ Brain : a journal of neurology 2007 PMID: 18055493
Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay. Krahn M Clinical genetics 2007 PMID: 17979987
A third of LGMD2A biopsies have normal calpain 3 proteolytic activity as determined by an in vitro assay. Milic A Neuromuscular disorders : NMD 2007 PMID: 17236769
Calpain-3 mutations in Turkey. Balci B European journal of pediatrics 2006 PMID: 16411092
Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. Piluso G Journal of medical genetics 2005 PMID: 16141003
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 - - - -

Text-mined citations for rs201892814...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 10, 2021