ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1318C>T (p.Arg440Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000070.3(CAPN3):c.1318C>T (p.Arg440Trp)
Variation ID: 283991 Accession: VCV000283991.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42399616 (GRCh38) [ NCBI UCSC ] 15: 42691814 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 26, 2017 Feb 20, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1318C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg440Trp missense NM_024344.2:c.1318C>T NP_077320.1:p.Arg440Trp missense NM_173087.2:c.1174C>T NP_775110.1:p.Arg392Trp missense NC_000015.10:g.42399616C>T NC_000015.9:g.42691814C>T NG_008660.1:g.56514C>T LRG_849:g.56514C>T LRG_849t1:c.1318C>T LRG_849p1:p.Arg440Trp P20807:p.Arg440Trp - Protein change
- R440W, R392W
- Other names
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- Canonical SPDI
- NC_000015.10:42399615:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CAPN3 | - | - |
GRCh38 GRCh37 |
1700 | 1839 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000269452.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000725372.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814145.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2023 | RCV003475903.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 16, 2018)
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criteria provided, single submitter
Method: research
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Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000778588.2 First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability, mild (present) , Global developmental delay (present) , Sleep disturbance (present)
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Likely pathogenic
(Nov 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000795542.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Pathogenic
(Apr 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000336423.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the musculature
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755540.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy, limb-girdle, autosomal dominant 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211513.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003822466.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000645467.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 440 of the CAPN3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 440 of the CAPN3 protein (p.Arg440Trp). This variant is present in population databases (rs777323132, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 11525884, 22926650, 26060040). ClinVar contains an entry for this variant (Variation ID: 283991). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg440 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15221789, 18055493, 19048948, 20694146, 21984748, 25326637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 18, 2020)
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no assertion criteria provided
Method: clinical testing
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Limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002085504.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical applications of next-generation sequencing-based gene panel in patients with muscular dystrophy: Korean experience. | Seong MW | Clinical genetics | 2016 | PMID: 26060040 |
Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
Genetic variability and clinical spectrum of Chinese patients with limb-girdle muscular dystrophy type 2A. | Luo SS | Muscle & nerve | 2012 | PMID: 22926650 |
Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity. | Sacconi S | Journal of medical genetics | 2012 | PMID: 21984748 |
Calpain 3 is a rapid-action, unidirectional proteolytic switch central to muscle remodeling. | de Morrée A | PloS one | 2010 | PMID: 20694146 |
[Case of LGMD2A (calpainopathy) clinically presenting as Miyoshi distal myopathy]. | Shirafuji T | Rinsho shinkeigaku = Clinical neurology | 2008 | PMID: 19048948 |
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. | Groen EJ | Brain : a journal of neurology | 2007 | PMID: 18055493 |
Molecular diagnosis in LGMD2A: mutation analysis or protein testing? | Fanin M | Human mutation | 2004 | PMID: 15221789 |
Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy. | Chae J | Neuromuscular disorders : NMD | 2001 | PMID: 11525884 |
Multiple independent molecular etiology for limb-girdle muscular dystrophy type 2A patients from various geographical origins. | Richard I | American journal of human genetics | 1997 | PMID: 9150160 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
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Text-mined citations for rs777323132 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.