ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.2092C>T (p.Arg698Cys)
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.2092C>T (p.Arg698Cys)
Variation ID: 285572 Accession: VCV000285572.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42409972 (GRCh38) [ NCBI UCSC ] 15: 42702170 (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 Jun 17, 2024 Apr 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.2092C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg698Cys missense NM_024344.2:c.2074C>T NP_077320.1:p.Arg692Cys missense NM_173087.2:c.1816C>T NP_775110.1:p.Arg606Cys missense NM_173088.2:c.556C>T NP_775111.1:p.Arg186Cys missense NM_173089.2:c.97C>T NP_775112.1:p.Arg33Cys missense NM_173090.2:c.97C>T NP_775113.1:p.Arg33Cys missense NC_000015.10:g.42409972C>T NC_000015.9:g.42702170C>T NG_008660.1:g.66870C>T LRG_849:g.66870C>T LRG_849t1:c.2092C>T LRG_849p1:p.Arg698Cys - Protein change
- R698C, R33C, R606C, R692C, R186C
- Other names
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- Canonical SPDI
- NC_000015.10:42409971: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
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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 |
1735 | 1877 |
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
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
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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 (2) |
criteria provided, single submitter
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Jan 3, 2020 | RCV000327815.10 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2024 | RCV000675154.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2023 | RCV003463760.2 |
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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Likely pathogenic
(Oct 14, 2022)
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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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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002600905.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
A homozygous variation in exon 19 of the CAPN3 gene that results in the amino acid substitution cysteine for arginine at codon 698 was detected. … (more)
A homozygous variation in exon 19 of the CAPN3 gene that results in the amino acid substitution cysteine for arginine at codon 698 was detected. The observed variant reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and MutationTaster2. The reference codon is conserved across species. (less)
Clinical Features:
Difficulty standing (present)
Age: 20-29 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Mar 07, 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:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014844.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The CAPN3 c.2092C>T (p.Arg698Cys) missense variant results in the substitution of arginine at amino acid position 698 with cysteine. This variant has been reported in … (more)
The CAPN3 c.2092C>T (p.Arg698Cys) missense variant results in the substitution of arginine at amino acid position 698 with cysteine. This variant has been reported in the literature in at least six individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD), including in a homozygous state in one individual and in a compound heterozygous state in five individuals (PMID: 16650086; PMID: 17236769; PMID: 21204801; PMID: 28403181; PMID: 33250842; PMID: 35169782). Additionally, two different amino acid substitutions at the same codon (Arg698His, Arg698Pro) have been reported in individuals with LGMD (PMID: 25135358; PMID: 10330340). This variant is reported in the Genome Aggregation Database at a frequency of 0.000029 in the Latino/Admixed American population (version 2.1.1). The c.2092C>T variant is located within EF-hand 2 domain, which has a low rate of benign variation (UniProt:P20807; PMID: 35169782). Based on the available evidence, the c.2092C>T (p.Arg698Cys) variant is classified as pathogenic for limb-girdle muscular dystrophy. (less)
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Pathogenic
(Jan 03, 2020)
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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: SCV002018043.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001376109.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 698 of the CAPN3 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 698 of the CAPN3 protein (p.Arg698Cys). This variant is present in population databases (rs764370512, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 16650086, 21204801, 28403181). ClinVar contains an entry for this variant (Variation ID: 285572). 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.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16411092, 25135358), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 11, 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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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164499.2
First in ClinVar: Mar 01, 2020 Last updated: Apr 15, 2024 |
Comment:
The homozygous p.Arg698Cys variant in CAPN3 was identified by our study in two unrelated individuals with limb-girdle muscular dystrophy (LGMD). The p.Arg698Cys variant has also … (more)
The homozygous p.Arg698Cys variant in CAPN3 was identified by our study in two unrelated individuals with limb-girdle muscular dystrophy (LGMD). The p.Arg698Cys variant has also been reported in at least 8 individuals with limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 16650086, 21204801, 28403181, 33250842, 35169782, 35821219), and has been identified in 0.002% (1/59994) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764370512). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 285572) and has been interpreted as likely pathogenic/pathogenic by multiple labs. Of the affected individuals, five were compound heterozygotes that carried reported pathogenic variant with unknown phase and two were homozygotes, which increases the likelihood that the p.Arg698Cys variant is pathogenic (Variation ID: 17621, 128570, 468648, 557732, 2680368; PMID: 17236769, 21204801, 28403181, 33250842, 35169782, 35821219). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Arg698Cys variant may slightly impact protein function (PMID: 17236769). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive limb-girdle muscular dystrophy. ACMG/AMP Criteria applied: PM3_strong, PP3_moderate, PM2_supporting, PS3_supporting (Richards 2015). (less)
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Pathogenic
(Dec 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: SCV004213778.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(May 10, 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: SCV000800764.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jan 22, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000338651.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India. | Ganaraja VH | Global medical genetics | 2021 | PMID: 35169782 |
Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. | Chakravorty S | Frontiers in neurology | 2020 | PMID: 33250842 |
Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing. | Yu M | PloS one | 2017 | PMID: 28403181 |
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
Eosinophilic infiltration related to CAPN3 mutations: a pathophysiological component of primary calpainopathy? | Krahn M | Clinical genetics | 2011 | PMID: 21204801 |
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 the CAPN3 gene in patients with possible LGMD2A. | Krahn M | Clinical genetics | 2006 | PMID: 16650086 |
Calpain-3 mutations in Turkey. | Balci B | European journal of pediatrics | 2006 | PMID: 16411092 |
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 |
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 rs764370512 ...
HelpRecord last updated Sep 29, 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.