ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1466G>A (p.Arg489Gln)
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.1466G>A (p.Arg489Gln)
Variation ID: 289644 Accession: VCV000289644.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42401752 (GRCh38) [ NCBI UCSC ] 15: 42693950 (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 26, 2024 May 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1466G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg489Gln missense NM_024344.2:c.1466G>A NP_077320.1:p.Arg489Gln missense NM_173087.2:c.1322G>A NP_775110.1:p.Arg441Gln missense NC_000015.10:g.42401752G>A NC_000015.9:g.42693950G>A NG_008660.1:g.58650G>A LRG_849:g.58650G>A LRG_849t1:c.1466G>A LRG_849p1:p.Arg489Gln P20807:p.Arg489Gln - Protein change
- R489Q, R441Q
- Other names
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- Canonical SPDI
- NC_000015.10:42401751: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD) 0.00016
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 (6) |
criteria provided, multiple submitters, no conflicts
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May 22, 2024 | RCV000350336.14 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2023 | RCV000517354.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 8, 2021 | RCV002504018.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 11, 2022 | RCV002509353.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2023 | RCV003475920.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2023 | RCV004535436.1 |
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
(Apr 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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Athena Diagnostics
Accession: SCV000612633.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Feb 09, 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: SCV000344033.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(May 21, 2019)
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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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GeneDx
Accession: SCV000616671.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 15, 2018 |
Comment:
Published functional studies demonstrate a damaging effect where normal autocatalytic calpain-3 activity was lost (Fanin et al., 2003); In silico analysis, which includes protein predictors … (more)
Published functional studies demonstrate a damaging effect where normal autocatalytic calpain-3 activity was lost (Fanin et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in two families from Reunion Island with LGMD and observed in an additional patient with LGMD who harbored a pathogenic variant on the opposite allele (in trans) in published literature (Richard et al., 1999; Fanin et al., 2003); This variant is associated with the following publications: (PMID: 16884488, 16971480, 17236769, 10330340, 14578192, 17994539, 15221789, 18854869, 30919934, 32668095) (less)
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Pathogenic
(Dec 07, 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: SCV002025061.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 24, 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: SCV001236695.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the CAPN3 protein (p.Arg489Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the CAPN3 protein (p.Arg489Gln). This variant is present in population databases (rs147764579, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 14578192, 17236769, 30919934). ClinVar contains an entry for this variant (Variation ID: 289644). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg489 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9762961, 16141003, 25135358, 27708273). 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
(May 01, 2018)
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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: SCV001247170.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2A
Muscular dystrophy, limb-girdle, autosomal dominant 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002800999.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 11, 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: SCV002819423.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: CAPN3 c.1466G>A (p.Arg489Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the … (more)
Variant summary: CAPN3 c.1466G>A (p.Arg489Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251278 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.1466G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Milic_2007, Bevilacqua_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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
(Feb 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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CAPN3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119057.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CAPN3 c.1466G>A variant is predicted to result in the amino acid substitution p.Arg489Gln. This variant has been repeatedly reported in the compound heterozygous or … (more)
The CAPN3 c.1466G>A variant is predicted to result in the amino acid substitution p.Arg489Gln. This variant has been repeatedly reported in the compound heterozygous or homozygous state in individuals with limb-girdle muscular dystrophy (Richard et al. 1999. PubMed ID: 10330340; Fanin et al. 2003. PubMed ID: 14578192; Supp. Table 1 in Ten Dam et al. 2019. PubMed ID: 30919934; https://databases.lovd.nl/shared/genes/CAPN3). Functional studies indicate this variant disrupts the normal autocatalytic activity (Fanin et al. 2003. PubMed ID: 14578192). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42693950-G-A). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 28, 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: SCV004211504.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 26, 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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807054.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(May 22, 2024)
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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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Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV004801906.2
First in ClinVar: Apr 06, 2024 Last updated: May 26, 2024 |
Comment:
PM2_Supporting: the highest population allele frequency in gnomAD v4.0 is 0.0006577 (0.06577%; 4/6082 alleles in Middle Eastern population) and there are no homozygous observations. PM1 … (more)
PM2_Supporting: the highest population allele frequency in gnomAD v4.0 is 0.0006577 (0.06577%; 4/6082 alleles in Middle Eastern population) and there are no homozygous observations. PM1 not met: pathogenic variants are distributed throughout the protein. PP3_moderate: REVEL score is 0.881. PM3 Met: 1.75 points awarded for 4 proband compound heterozygous occurrences of variant (not confirmed in trans) (PMID: 30919934, 14578192). PM5 met: Other variants that disrupt this Arg residue known to be pathogenic (PMID: 9762961, 16141003, 25135358, 27708273). PS3_Supporting: Functional studies show CAPN3 Arg489Gln variant results in loss of normal autocatalytic calpain-3 activity (PMID:14578192) and a shorter CAPN3 transcript due to predicted exon skipping by minigene assay (PMID:32668095). PS4_Supporting: Variant identified in 3 probands with consistent phenotype for disorder (PMID: 10330340, 31931849). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: South Africa
Comment on evidence:
Proband carries a second uncertain significance CAPN3NM_000070.3:c.1240T>G(p.Cys414Gly) variant (not confirmed in trans).
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Likely pathogenic
(Mar 15, 2018)
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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: SCV000798519.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
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Pathogenic
(Mar 26, 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: SCV002085514.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002015204.2
First in ClinVar: Nov 20, 2021 Last updated: Oct 01, 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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The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia. | Mahungu AC | Frontiers in neurology | 2023 | PMID: 37712079 |
Calpainopathy. | Adam MP | - | 2022 | PMID: 20301490 |
Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay. | Dionnet E | Human mutation | 2020 | PMID: 32668095 |
The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease. | Bevilacqua JA | Orphanet journal of rare diseases | 2020 | PMID: 31931849 |
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. | Ten Dam L | Clinical genetics | 2019 | PMID: 30919934 |
The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. | Reddy HM | Journal of human genetics | 2017 | PMID: 27708273 |
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 |
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
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 |
Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations. | Fanin M | Journal of medical genetics | 2007 | PMID: 16971480 |
Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. | Piluso G | Journal of medical genetics | 2005 | PMID: 16141003 |
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 |
Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression. | Fanin M | The American journal of pathology | 2003 | PMID: 14578192 |
Calpainopathy-a survey of mutations and polymorphisms. | Richard I | American journal of human genetics | 1999 | PMID: 10330340 |
Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). | Urtasun M | Brain : a journal of neurology | 1998 | PMID: 9762961 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
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Text-mined citations for rs147764579 ...
HelpRecord last updated Jun 02, 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.