ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1250C>T (p.Thr417Met)
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.1250C>T (p.Thr417Met)
Variation ID: 281505 Accession: VCV000281505.71
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42691746 (GRCh37) [ NCBI UCSC ] 15: 42399548 (GRCh38) [ 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 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1250C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Thr417Met missense NM_024344.2:c.1250C>T NP_077320.1:p.Thr417Met missense NM_173087.2:c.1106C>T NP_775110.1:p.Thr369Met missense NC_000015.10:g.42399548C>T NC_000015.9:g.42691746C>T NG_008660.1:g.56446C>T LRG_849:g.56446C>T LRG_849t1:c.1250C>T LRG_849p1:p.Thr417Met - Protein change
- T417M, T369M
- Other names
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- Canonical SPDI
- NC_000015.10:42399547: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000340100.15 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000724905.34 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814141.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2022 | RCV002509343.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2022 | RCV002502096.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 15, 2023 | RCV003475890.1 |
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 12, 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: SCV000332311.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
Sex: mixed
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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:
de novo
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164477.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Thr417Met variant in CAPN3 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle … (more)
The heterozygous p.Thr417Met variant in CAPN3 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) Trio exome analysis showed this variant to be de novo. The p.Thr417Met variant in CAPN3 has been reported in 4 individuals (including 1 French, 1 European Canadian individual) with LGMD (PMID: 25135358, 25079074,16650086), and has been identified in 0.008324% (2/24026) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200646556). 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. Animal models in rats have shown that this variant impacts calcium binding for the protein and causes LGMD (PMID: 19226146). The presence of this variant in combination with 2 reported pathogenic variants, p.Thr184Argfs and p.Glu622Argfs, and in 2 individuals with LGMD increases the likelihood that the p.Thr417Met variant is pathogenic (Variation ID: 17621, 290296). This variant has also been reported pathogenic in ClinVar (Variation ID: 281505). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant, functional evidence, and multiple occurrences with pathogenic CAPN3 variants in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PS2, PP3, PM3_Strong, PS3_Moderate (Richards 2015). (less)
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Pathogenic
(Jun 02, 2020)
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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: SCV001476310.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is … (more)
The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (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: SCV001755319.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Likely pathogenic
(Jun 22, 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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GeneDx
Accession: SCV001871047.3
First in ClinVar: Sep 19, 2021 Last updated: Jul 01, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25135358, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25135358, 19226146, 15689361, 19556129, 25214167, 25079074, 16650086, 32703463, 29792937, 31788660, 32528171, 32668095, Koken_2022_Abstract, 34440373) (less)
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Likely pathogenic
(Oct 12, 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: SCV002025058.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 27, 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: SCV000823944.8
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 417 of the CAPN3 protein (p.Thr417Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 417 of the CAPN3 protein (p.Thr417Met). This variant is present in population databases (rs200646556, gnomAD 0.008%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 20517216, 25079074, 25135358). ClinVar contains an entry for this variant (Variation ID: 281505). 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: 19226146). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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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: SCV001247166.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
CAPN3: PM3:Very Strong, PM2, PP3, PS3:Supporting
Number of individuals with the variant: 9
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Pathogenic
(Apr 30, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520051.1
First in ClinVar: May 27, 2022 Last updated: May 27, 2022 |
Comment:
PS3, PM2, PS4_moderate, PP3, PP4
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Pathogenic
(Mar 08, 2022)
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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: SCV002808724.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 02, 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: SCV002819385.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: CAPN3 c.1250C>T (p.Thr417Met) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein … (more)
Variant summary: CAPN3 c.1250C>T (p.Thr417Met) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) 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 5.2e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.2e-05 vs 0.0032), allowing no conclusion about variant significance. c.1250C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 15689361, 18258189, 25135358, 27447704, 34440373, 25079074, 16650086). 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. Multiple clinical diagnostic laboratories have submitted 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
(Oct 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: SCV004211535.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Mar 01, 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: SCV000790013.2
First in ClinVar: Dec 06, 2016 Last updated: Aug 13, 2019 |
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Likely 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: SCV001454338.1
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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An Integrated Clinical-Biological Approach to Identify Interindividual Variability and Atypical Phenotype-Genotype Correlations in Myopathies: Experience on A Cohort of 156 Families. | Juntas Morales R | Genes | 2021 | PMID: 34440373 |
Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay. | Dionnet E | Human mutation | 2020 | PMID: 32668095 |
Phenotypic and genetic spectrum of patients with limb-girdle muscular dystrophy type 2A from Serbia. | Peric S | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2019 | PMID: 31788660 |
Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic. | Stehlíková K | Clinical genetics | 2017 | PMID: 27447704 |
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
Redox state and mitochondrial respiratory chain function in skeletal muscle of LGMD2A patients. | Nilsson MI | PloS one | 2014 | PMID: 25079074 |
[Clinical-genetic characteristics of limb girdle-muscular dystrophy type 2A]. | Dadali EL | Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova | 2010 | PMID: 20517216 |
Immunohistochemical analysis of calpain 3: advantages and limitations in diagnosing LGMD2A. | Charlton R | Neuromuscular disorders : NMD | 2009 | PMID: 19556129 |
Limb-girdle muscular dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3. | Garnham CP | Biochemistry | 2009 | PMID: 19226146 |
The importance of conserved amino acid residues in p94 protease sub-domain IIb and the IS2 region for constitutive autolysis. | Ono Y | FEBS letters | 2008 | PMID: 18258189 |
Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients. | Hanisch F | Clinical neuropathology | 2007 | PMID: 17702496 |
Screening of the CAPN3 gene in patients with possible LGMD2A. | Krahn M | Clinical genetics | 2006 | PMID: 16650086 |
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 |
Deconvolution of emission tomographic data: a clinical evaluation. | Yanch JC | The British journal of radiology | 1988 | PMID: 3258171 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 | - | - | - | - |
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Text-mined citations for rs200646556 ...
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.