ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1477C>T (p.Arg493Trp)
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.1477C>T (p.Arg493Trp)
Variation ID: 193792 Accession: VCV000193792.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42401763 (GRCh38) [ NCBI UCSC ] 15: 42693961 (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 Jun 29, 2015 Feb 14, 2024 Jan 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1477C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg493Trp missense NM_024344.2:c.1477C>T NP_077320.1:p.Arg493Trp missense NM_173087.2:c.1333C>T NP_775110.1:p.Arg445Trp missense NC_000015.10:g.42401763C>T NC_000015.9:g.42693961C>T NG_008660.1:g.58661C>T LRG_849:g.58661C>T LRG_849t1:c.1477C>T LRG_849p1:p.Arg493Trp P20807:p.Arg493Trp - Protein change
- R493W, R445W
- Other names
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- Canonical SPDI
- NC_000015.10:42401762: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 |
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Aug 2, 2022 | RCV000173976.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV000201107.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 15, 2023 | RCV003462275.1 |
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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Pathogenic
(Aug 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000255655.4
First in ClinVar: Jun 29, 2015 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with LGMD, this variant has been seen with … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with LGMD, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047724.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The CAPN3 c.1477C>T variant has been reported in individuals affected with Muscular dystrophy, limb-girdle, autosomal recessive 1 (Nilsson et. al., 2014; Benayoun et. al., 2008). … (more)
The CAPN3 c.1477C>T variant has been reported in individuals affected with Muscular dystrophy, limb-girdle, autosomal recessive 1 (Nilsson et. al., 2014; Benayoun et. al., 2008). The p.Arg493Trp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002832% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. The amino acid Arg at position 493 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Myopathy (present)
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Pathogenic
(Jun 15, 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: SCV004213766.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 12, 2024)
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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: SCV001387850.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 493 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 493 of the CAPN3 protein (p.Arg493Trp). This variant is present in population databases (rs557164942, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 17236769, 18073330, 18334579, 25079074). ClinVar contains an entry for this variant (Variation ID: 193792). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 18, 2016)
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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: SCV000331924.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 4
Sex: mixed
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Likely pathogenic
(Apr 27, 2021)
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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: SCV002025071.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(May 31, 2017)
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no assertion criteria provided
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: SCV000791903.2
First in ClinVar: Dec 15, 2017 Last updated: Jul 30, 2019 |
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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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Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders. | Park HJ | Clinical genetics | 2017 | PMID: 27363342 |
Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients. | Nilsson MI | PloS one | 2014 | PMID: 25079074 |
Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. | Huang Y | Human molecular genetics | 2008 | PMID: 18334579 |
NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. | Benayoun B | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2008 | PMID: 18073330 |
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. | Groen EJ | Brain : a journal of neurology | 2007 | PMID: 18055493 |
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 |
Calpainopathy-a survey of mutations and polymorphisms. | Richard I | American journal of human genetics | 1999 | PMID: 10330340 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
Text-mined citations for rs557164942 ...
HelpRecord last updated May 08, 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.