ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1333G>A (p.Gly445Arg)
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.1333G>A (p.Gly445Arg)
Variation ID: 284515 Accession: VCV000284515.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42399631 (GRCh38) [ NCBI UCSC ] 15: 42691829 (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 6, 2016 May 12, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1333G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Gly445Arg missense NM_024344.2:c.1333G>A NP_077320.1:p.Gly445Arg missense NM_173087.2:c.1189G>A NP_775110.1:p.Gly397Arg missense NC_000015.10:g.42399631G>A NC_000015.9:g.42691829G>A NG_008660.1:g.56529G>A LRG_849:g.56529G>A LRG_849t1:c.1333G>A LRG_849p1:p.Gly445Arg P20807:p.Gly445Arg - Protein change
- G445R, G397R
- Other names
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- Canonical SPDI
- NC_000015.10:42399630:G:A
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Jan 16, 2024 | RCV000405059.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV000725472.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 9, 2022 | RCV002282104.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV003475905.1 |
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
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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
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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
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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
(Mar 28, 2017)
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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: SCV000337170.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
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Likely pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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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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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164533.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Gly445Arg variant in CAPN3 was identified by our study in two unrelated individuals in the compound heterozygous state, with a pathogenic variant, in … (more)
The heterozygous p.Gly445Arg variant in CAPN3 was identified by our study in two unrelated individuals in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006295% (4/63542) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773827877). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. There are several individuals in the literature with LGMD and this variant in either the compound heterozygous state or with no other known causative variant (PMID: 17994539). In summary, although additional studies are required to fully establish its clinical significance, the clinical significance of the p.Gly445Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP3 (Richards 2015). (less)
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Pathogenic
(Jul 19, 2023)
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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: SCV002018063.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 16, 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: SCV000953639.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 445 of the CAPN3 protein (p.Gly445Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 445 of the CAPN3 protein (p.Gly445Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 10330340, 15221789, 17236769, 18854869; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 284515). 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%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15221789, 17236769, 20635405). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002571894.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: CAPN3 c.1333G>A (p.Gly445Arg) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the … (more)
Variant summary: CAPN3 c.1333G>A (p.Gly445Arg) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 240268 control chromosomes. c.1333G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, with recent reports associating this variant with an autosomal dominant mode of inheritance (example, Saenz_2005, Avila_2015, Guglieri_2008, Aguennouz_2016, Cerino_2020, Macias_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating that the variant impacts calpain-3 catalytic activity and intra/intermolecular autolysis (Cerino_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 02, 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: SCV004211553.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 03, 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: SCV004229510.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in multiple individuals with apparently autosomal … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in multiple individuals with apparently autosomal recessive LGMD (PMID: 10330340, 17994539, 20635405). It has also been reported to segregate with autosomal dominant LGMD in several families (PMID: 32342993). Experiments in patient-derived samples showed absence or significant reduction in CAPN3 protein level/activity in multiple patients. (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033373.6
First in ClinVar: Sep 16, 2023 Last updated: May 12, 2024 |
Comment:
CAPN3: PP1:Strong, PS1, PM1, PP3, PS3:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 02, 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: SCV000791979.2
First in ClinVar: Dec 06, 2016 Last updated: Aug 14, 2019 |
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Pathogenic
(Sep 16, 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: SCV001454340.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Targeted Next-Generation Sequencing Reveals Mutations in Non-coding Regions and Potential Regulatory Sequences of Calpain-3 Gene in Polish Limb-Girdle Muscular Dystrophy Patients. | Macias A | Frontiers in neuroscience | 2021 | PMID: 34720847 |
Novel CAPN3 variant associated with an autosomal dominant calpainopathy. | Cerino M | Neuropathology and applied neurobiology | 2020 | PMID: 32342993 |
MicroRNA signatures predict dysregulated vitamin D receptor and calcium pathways status in limb girdle muscle dystrophies (LGMD) 2A/2B. | Aguennouz M | Cell biochemistry and function | 2016 | PMID: 27558075 |
ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases. | Magri F | BMC neurology | 2015 | PMID: 26404900 |
Neuromuscular Pathology Case. | Avila JD | Journal of clinical neuromuscular disease | 2015 | PMID: 26301378 |
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 |
How to tackle the diagnosis of limb-girdle muscular dystrophy 2A. | Fanin M | European journal of human genetics : EJHG | 2009 | PMID: 18854869 |
Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. | Guglieri M | Human mutation | 2008 | PMID: 17994539 |
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 |
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. | Sáenz A | Brain : a journal of neurology | 2005 | PMID: 15689361 |
Molecular diagnosis in LGMD2A: mutation analysis or protein testing? | Fanin M | Human mutation | 2004 | PMID: 15221789 |
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 | - | - | - | - |
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Text-mined citations for rs773827877 ...
HelpRecord last updated May 12, 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.