ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3490+1G>T
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_000256.3(MYBPC3):c.3490+1G>T
Variation ID: 181008 Accession: VCV000181008.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332813 (GRCh38) [ NCBI UCSC ] 11: 47354364 (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 7, 2017 Feb 14, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3490+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000011.10:g.47332813C>A NC_000011.9:g.47354364C>A NG_007667.1:g.24890G>T LRG_386:g.24890G>T LRG_386t1:c.3490+1G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:47332812:C: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.
The Genome Aggregation Database (gnomAD) 0.00001
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 |
3858 | 3875 |
Conditions - Germline
Condition
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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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Pathogenic (3) |
criteria provided, single submitter
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Oct 24, 2022 | RCV000158238.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2024 | RCV000628980.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 8, 2018 | RCV000779061.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 15, 2021 | RCV001375509.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002453538.2 |
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
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
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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 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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MYBPC3-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915527.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYBPC3 c.3490+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.3490+1G>T … (more)
The MYBPC3 c.3490+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.3490+1G>T variant has been reported in two studies in which it is found in a total of seven individuals, including six individuals with either dilated or hypertrophic cardiomyopathy from the same family (Zeller et al. 2006; Ehlermann et al. 2008). Another family member who experienced sudden death at the age of 32 was an obligate carrier of the variant based on family history and pedigree analysis. The variant was not found among 430 control individuals with normal systolic and diastolic function, nor was it found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database (Ehlermann et al. 2008). Based on the evidence including the potential impact of splice donor variants, the c.3490+1G>T variant is classified as likely pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Oct 04, 2018)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001156329.1
First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020 |
Comment:
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this … (more)
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. (less)
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Pathogenic
(Apr 15, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001572357.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
Variant summary: MYBPC3 c.3490+1G>T (also reported as IVS32+1 G>T, IVS31+1 G>T) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting … (more)
Variant summary: MYBPC3 c.3490+1G>T (also reported as IVS32+1 G>T, IVS31+1 G>T) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. One predicts the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 233146 control chromosomes (gnomAD). c.3490+1G>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (both hypertrophic and dilated cardiomyopathy) including in a family with clear segregation of the variant with the disease (example: Zeller_2006, Ehlermann_2008, Hershberger_2010, Hoedemaekers_2007, Ross_2017). 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. Four ClinVar submitters (evaluation after 2014) cite 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 24, 2022)
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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: SCV000208173.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17947214, 28615295, 20215591, 18957093, 16715312, 25163546, 29121657) (less)
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002616092.2
First in ClinVar: Nov 29, 2022 Last updated: Apr 15, 2023 |
Comment:
The c.3490+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant was … (more)
The c.3490+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant was identified in multiple individuals with hypertrophic or dilated cardiomyopathy (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:e001671; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948) and was shown to segregate with disease in one family (Zeller R et al. J. Mol. Med., 2006 Aug;84:682-91; Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Jan 03, 2024)
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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: SCV000749890.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy and/or hyperthrophic cardiomyopathy (PMID: 16715312, 28615295, 29121657). It has also been observed to segregate with disease in related individuals. This variant is also known as intron 32+1G>T. ClinVar contains an entry for this variant (Variation ID: 181008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely 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: SCV001954466.1 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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969691.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 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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Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
Atlas of the clinical genetics of human dilated cardiomyopathy. | Haas J | European heart journal | 2015 | PMID: 25163546 |
Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. | Hershberger RE | Circulation. Cardiovascular genetics | 2010 | PMID: 20215591 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. | Ehlermann P | BMC medical genetics | 2008 | PMID: 18957093 |
Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies. | Hoedemaekers YM | European heart journal | 2007 | PMID: 17947214 |
Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE. | Zeller R | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16715312 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs397516020 ...
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.