ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.1194-9A>G
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.1194-9A>G
Variation ID: 217146 Accession: VCV000217146.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q15.1 15: 42399483 (GRCh38) [ NCBI UCSC ] 15: 42691681 (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 15, 2017 Feb 14, 2024 Nov 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000070.3:c.1194-9A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_024344.2:c.1194-9A>G intron variant NM_173087.2:c.1050-9A>G intron variant NC_000015.10:g.42399483A>G NC_000015.9:g.42691681A>G NG_008660.1:g.56381A>G LRG_849:g.56381A>G LRG_849t1:c.1194-9A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000015.10:42399482:A:G
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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 (3) |
criteria provided, single submitter
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Nov 6, 2023 | RCV000201038.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 24, 2023 | RCV000516175.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2023 | RCV003474967.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV003225933.2 |
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
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: SCV000255648.3
First in ClinVar: Oct 19, 2015 Last updated: Dec 19, 2017 |
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Pathogenic
(Oct 10, 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: SCV000338518.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(Apr 24, 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: SCV002102621.3
First in ClinVar: Mar 12, 2022 Last updated: Apr 30, 2023 |
Comment:
Published functional studies demonstrate a damaging effect by impairing splicing causing at least a partial intron 9 retention (Salem et al., 2012); This variant is … (more)
Published functional studies demonstrate a damaging effect by impairing splicing causing at least a partial intron 9 retention (Salem et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 10330340, 22158424, 33335567, 34720847, 32528171, 31788660, 25135358, 27500519, 30919934, 28403181, 11525884, 26404900) (less)
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Autosomal recessive limb-girdle muscular dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922313.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous c.1194-9A>G variant in CAPN3 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 17622), in … (more)
The heterozygous c.1194-9A>G variant in CAPN3 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 17622), in one individual with limb-girdle muscular dystrophy. This individual also carried a pathogenic variant (ClinVar Variation ID: 17622), however the phase of these variants are unknown at this time. The c.1194-9A>G variant in CAPN3 has been previously reported in twelve individuals with autosomal recessive limb-girdle muscular dystrophy 1 (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), segregated with disease in 3 affected relatives from one family (PMID: 22158424), but has been identified in 0.006% (1/16256) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374665929). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217146) and has been interpreted as pathogenic by PerkinElmer Genomics, Natera, Inc, Athena Diagnostics, Invitae, and Eurofins NTD LLC, and as likely pathogenic by Counsyl and GeneDx. Of these twelve affected individuals previously reported (PMID: 25135358, PMID: 27066573, PMID: 10330340, PMID: 10330340, PMID: 31788660, PMID: 32528171, PMID: 30919934, PMID: 34720847, PMID: 33335567, PMID: 18055493, PMID: 11525884, PMID: 22158424, PMID: 12461690), 6 were homozygotes (PMID: 10330340, PMID: 30919934, PMID: 22158424, PMID: 12461690, PMID: 11525884, PMID: 30919934) , two were compound heterozygotes who carried pathogenic variants in trans (PMID: 25135358, PMID: 31788660), one was a compound heterozygote who carried a likely pathogenic variant in unknown phase (PMID: 18055493), and four were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 25135358, PMID: 27066573, PMID: 34720847), and, in addition, the individual identified by our study was a compound heterozygote who carried a pathogenic variant (ClinVar Variation ID: 17622) in unknown phase, which increases the likelihood that the c.1194-9A>G variant is pathogenic. RT-PCR analysis performed on RNA from an affected individual’s muscle biopsy showed altered splicing, with incorporation of eight nucleotides from intron 9 in a transcript lacking the seven first exons, versus the wild-type transcript seen in RNA from a muscle biopsy of a unaffected control individual (PMID: 22158424). This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive limb-girdle muscular dystrophy 1. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP1 (Richards 2015). (less)
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Pathogenic
(Oct 20, 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: SCV004211520.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 22, 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: SCV002018074.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 06, 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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Invitae
Accession: SCV000766706.8
First in ClinVar: Dec 15, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 9 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. … (more)
This sequence change falls in intron 9 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs374665929, gnomAD 0.007%). This variant has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 11525884, 12461690, 18055493, 22158424, 25135358). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217146). Studies have shown that this variant results in the retention of 8 nucleotides of intron 9 and introduces a premature termination codon (PMID: 22158424). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Sep 11, 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: SCV000793873.2
First in ClinVar: Dec 15, 2017 Last updated: Dec 23, 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: SCV001454336.1
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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Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. | Izumi R | Neurology. Genetics | 2015 | PMID: 27066573 |
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. | Stehlíková K | BMC neurology | 2014 | PMID: 25135358 |
CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements. | Salem IH | Journal of human genetics | 2012 | PMID: 22158424 |
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A. | Groen EJ | Brain : a journal of neurology | 2007 | PMID: 18055493 |
Clinical variability in calpainopathy: what makes the difference? | de Paula F | European journal of human genetics : EJHG | 2002 | PMID: 12461690 |
Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy. | Chae J | Neuromuscular disorders : NMD | 2001 | PMID: 11525884 |
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 | - | - | - | - |
Text-mined citations for rs374665929 ...
HelpRecord last updated May 08, 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.