ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.146G>A (p.Arg49His)
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.146G>A (p.Arg49His)
Variation ID: 217151 Accession: VCV000217151.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42359951 (GRCh38) [ NCBI UCSC ] 15: 42652149 (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 Oct 19, 2015 Jun 17, 2024 Nov 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.146G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Arg49His missense NM_024344.2:c.146G>A NP_077320.1:p.Arg49His missense NM_173087.2:c.146G>A NP_775110.1:p.Arg49His missense NC_000015.10:g.42359951G>A NC_000015.9:g.42652149G>A NG_008660.1:g.16849G>A LRG_849:g.16849G>A LRG_849t1:c.146G>A LRG_849p1:p.Arg49His - Protein change
- R49H
- Other names
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- Canonical SPDI
- NC_000015.10:42359950: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.
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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 |
1730 | 1872 |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 9, 2023 | RCV000201045.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2020 | RCV001781586.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2023 | RCV003330572.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814106.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV003474971.2 |
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
(Aug 27, 2015)
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criteria provided, single submitter
Method: clinical testing
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Limb-girdle muscular dystrophy, type 2A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255654.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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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: SCV001164521.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The homozygous p.Arg49His variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large … (more)
The homozygous p.Arg49His variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg49His variant in CAPN3 has been reported in the compound heterozygous state in 5 individuals with LGMD (PMID: 17318636, 16650086, 16100770, 16411092). The presence of this variant in combination with multiple CAPN3 variants (1 reported pathogenic, 2 reported VUS, and 2 loss of function variants not reported in ClinVar) and in 5 individuals with LGMD increases the likelihood that the p.Arg49His variant is pathogenic. Another missense variant at the same position, p.Arg49Cys, has been reported likely pathogenic in ClinVar (Variation ID: 193037). This raises the possibility that a change at this position would not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong, PM4_Supporting (Richards 2015). (less)
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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: SCV001755679.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Likely pathogenic
(Oct 20, 2022)
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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: yes
Allele origin:
germline
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Eurofins-Biomnis
Accession: SCV003935050.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
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Pathogenic
(Aug 10, 2023)
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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: SCV004038535.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: CAPN3 c.146G>A (p.Arg49His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: CAPN3 c.146G>A (p.Arg49His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes (gnomAD). c.146G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Krahn_2007, Monies-2016, Saat_2021, and Ozyilmaz_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35157181, 27671536, 33963534, 16650086). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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
(Jan 04, 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: SCV002018091.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 09, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001405410.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 217151). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the CAPN3 protein (p.Arg49His). (less)
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Pathogenic
(Nov 29, 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: SCV004211563.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jan 31, 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: SCV000797544.2
First in ClinVar: Oct 19, 2015 Last updated: Dec 23, 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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Experiences in the molecular genetic and histopathological evaluation of calpainopathies. | Ozyilmaz B | Neurogenetics | 2022 | PMID: 35157181 |
Mutation spectrum of hereditary myopathies in Turkish patients and novel variants. | Saat H | Annals of human genetics | 2021 | PMID: 33963534 |
A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies. | Monies D | Human genomics | 2016 | PMID: 27671536 |
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A. | Charlton R | Neuromuscular disorders : NMD | 2009 | PMID: 19556129 |
Eosinophilic myositis in calpainopathy: could immunosuppression of the eosinophilic myositis alter the early natural course of the dystrophic disease? | Oflazer PS | Neuromuscular disorders : NMD | 2009 | PMID: 19285864 |
Phenotypic variability in siblings with calpainopathy (LGMD2A). | Schessl J | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2008 | PMID: 19364062 |
Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. | Huang Y | Human molecular genetics | 2008 | PMID: 18334579 |
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. | Groen EJ | Brain : a journal of neurology | 2007 | PMID: 18055493 |
A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients. | Todorova A | Neurogenetics | 2007 | PMID: 17318636 |
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 |
Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. | Piluso G | Journal of medical genetics | 2005 | PMID: 16141003 |
Calpainopathy (LGMD2A) in Croatia: molecular and haplotype analysis. | Milic A | Croatian medical journal | 2005 | PMID: 16100770 |
Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia. | Canki-Klain N | American journal of medical genetics. Part A | 2004 | PMID: 14981715 |
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Text-mined citations for rs863224958 ...
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.