ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1458-6G>A
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.
Pathogenic(2); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000256.3(MYBPC3):c.1458-6G>A
Variation ID: 42533 Accession: VCV000042533.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47342750 (GRCh38) [ NCBI UCSC ] 11: 47364301 (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 Jan 31, 2015 Feb 14, 2024 Feb 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1458-6G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.47342750C>T NC_000011.9:g.47364301C>T NG_007667.1:g.14953G>A LRG_386:g.14953G>A LRG_386t1:c.1458-6G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:47342749: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.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3890 | 3907 |
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
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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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 29, 2019 | RCV000035399.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 7, 2015 | RCV000157325.2 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2022 | RCV000230101.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 31, 2017 | RCV000600435.5 | |
Uncertain significance (4) |
criteria provided, single submitter
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Sep 8, 2020 | RCV000766336.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 15, 2023 | RCV000770369.3 |
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
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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Uncertain significance
(Jan 07, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207060.3
First in ClinVar: Feb 06, 2015 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 2
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Uncertain significance
(Sep 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901810.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Pathogenic
(Apr 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743563.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(May 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744853.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, University of Leuven
Accession: SCV000886821.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Uncertain significance
(Aug 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059047.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The c.1458-6G>A variant has been reported in 1 family with HCM that also carried a second variant in MYH7 (Arg694Cys) that was felt to be … (more)
The c.1458-6G>A variant has been reported in 1 family with HCM that also carried a second variant in MYH7 (Arg694Cys) that was felt to be the primary cause of disease (Andersen 2004). In addition, this variant was identified in 3 individuals with HCM, one of whom carried a pathogenic MYBPC3 variant (LMM data). It has also been identified in 10/248536 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42533). This variant is located in the 3' splice region and computational tools predict a possible impact on splicing. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3. (less)
Number of individuals with the variant: 7
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Uncertain significance
(Sep 08, 2020)
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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: SCV000208024.4
First in ClinVar: Feb 24, 2015 Last updated: May 02, 2019 |
Comment:
Reported in two affected individuals from one family with HCM, however, both of these individuals also harbored a missense variant in the MYH7 gene and … (more)
Reported in two affected individuals from one family with HCM, however, both of these individuals also harbored a missense variant in the MYH7 gene and an additional affected relative harbored only the MYH7 missense variant (Havndrup et al., 2013); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 42533; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15114369, 31513939, 12566107, 29121657, 28679633, 31737537, 30847666) (less)
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Uncertain significance
(Oct 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284212.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change falls in intron 16 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. … (more)
This sequence change falls in intron 16 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs375347534, gnomAD 0.007%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12566107, 15114369, 31513939; Invitae). This variant is also known as g.10899G>A and IVS16-6G>A. ClinVar contains an entry for this variant (Variation ID: 42533). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (PMID: 28679633). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358726.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the -6 position of intron 16 of the MYBPC3 gene. Splice site prediction tools predict … (more)
This variant causes a G to A nucleotide substitution at the -6 position of intron 16 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four unrelated individuals affected with hypertrophic cardiomyopathy, one of whom also carried a pathogenic variant in the MYH7 gene (PMID: 15114369, 19035361, 31513939, 36082122). This variant has been identified in 10/248536 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956777.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733051.4 First in ClinVar: Apr 09, 2018 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001923061.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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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Transcriptional bursts and heterogeneity among cardiomyocytes in hypertrophic cardiomyopathy. | Burkart V | Frontiers in cardiovascular medicine | 2022 | PMID: 36082122 |
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. | Ito K | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28679633 |
Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. | Andersen PS | Human mutation | 2009 | PMID: 19035361 |
Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency. | Andersen PS | European journal of human genetics : EJHG | 2004 | PMID: 15114369 |
Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations. | Havndrup O | Cardiovascular research | 2003 | PMID: 12566107 |
Text-mined citations for rs375347534 ...
HelpRecord last updated Feb 20, 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.