ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3642G>A (p.Trp1214Ter)
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.3642G>A (p.Trp1214Ter)
Variation ID: 162506 Accession: VCV000162506.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332244 (GRCh38) [ NCBI UCSC ] 11: 47353795 (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 Nov 5, 2015 Apr 15, 2024 Feb 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3642G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Trp1214Ter nonsense NC_000011.10:g.47332244C>T NC_000011.9:g.47353795C>T NG_007667.1:g.25459G>A LRG_386:g.25459G>A LRG_386t1:c.3642G>A LRG_386p1:p.Trp1214Ter - Protein change
- W1214*
- Other names
- p.W1214*:TGG>TGA
- Canonical SPDI
- NC_000011.10:47332243: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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
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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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3679 | 3696 |
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
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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, multiple submitters, no conflicts
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Jul 1, 2023 | RCV000158241.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV000201437.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000206843.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 15, 2020 | RCV001263457.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 20, 2019 | RCV001179298.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2020 | RCV002453476.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 16, 2021 | RCV002478419.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2024 | RCV003952708.1 |
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
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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
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256182.1 First in ClinVar: Nov 05, 2015 Last updated: Nov 05, 2015 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 01, 2014)
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criteria provided, single submitter
Method: research
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000196741.2 First in ClinVar: Jan 18, 2015 Last updated: Jan 31, 2016 |
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Pathogenic
(Jan 26, 2017)
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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: SCV000208176.9
First in ClinVar: Feb 24, 2015 Last updated: Mar 08, 2017 |
Comment:
The W1214X variant in the MYBPC3 gene has been reported in an Indian male patient with familial HCM who also harbored another variant in the … (more)
The W1214X variant in the MYBPC3 gene has been reported in an Indian male patient with familial HCM who also harbored another variant in the MYH7 gene (Bashyam M et al., 2012). The variant was absent from 100 ethnically matched control individuals. W1214X is predicted to cause loss of normal protein function either by protein truncation or nonsense mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in association with HCM. In summary, W1214X in the MYBPC3 gene is interpreted as a disease-causing variant. (less)
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Likely pathogenic
(Oct 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction cardiomyopathy
Primary dilated cardiomyopathy (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV001441524.1
First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020 |
Comment:
We observed a c.3642G>A (p.W1214*) genetic variant in a 30-y.o. female proband, diagnosed with non-compaction cardiomyopathy, dilatation of cardiac chambers and heart rhythm disturbances. The … (more)
We observed a c.3642G>A (p.W1214*) genetic variant in a 30-y.o. female proband, diagnosed with non-compaction cardiomyopathy, dilatation of cardiac chambers and heart rhythm disturbances. The proband also carried the additional variant of unknown clinical significance in MYBPC3 gene - p.P186L in heterozygous state. The family was unavailable for screening. The p.W1214* genetic variant is a nonsense mutation in the MYBPC3 gene. No functional studies are available for the p.W1214* variant, however, nonsense variants in MYBPC3 gene are well-known to cause cardiomyopathy through haploinsufficiency. According to Cardio Classifier predictions, mRNA carrying the p.W1214* variant, will be processed through nonsence-mediated decay mechanism, leading to haploinsufficiency. We assume that the p.W1214* variant could be classified as likely pathogenic. (less)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasian
Comment on evidence:
Proband was diagnosed with left ventricular non-compaction syndrome and dilatation cardiomyopathy.
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447398.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypertrophic cardiomyopathy (present)
Sex: female
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Pathogenic
(Aug 20, 2019)
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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: SCV001343928.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. A different variant (c.3641G>A) resulting in the same protein effect (p.Trp1214*) has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21959974, 24093860). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 02, 2020)
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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: SCV002613761.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.W1214* pathogenic mutation (also known as c.3642G>A), located in coding exon 33 of the MYBPC3 gene, results from a G to A substitution at … (more)
The p.W1214* pathogenic mutation (also known as c.3642G>A), located in coding exon 33 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3642. This changes the amino acid from a tryptophan to a stop codon within coding exon 33. This mutation has been reported in hypertrophic cardiomyopathy (HCM) cohorts, including one HCM case with an additional MYH7 variant also detected (Bashyam MD et al. Mol. Cell. Biochem., 2012 Jan;360:373-82; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002777575.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 01, 2023)
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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: SCV000259243.6
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp1214*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp1214*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs368765949, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21959974, 24093860). ClinVar contains an entry for this variant (Variation ID: 162506). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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MYBPC3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004770914.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MYBPC3 c.3642G>A variant is predicted to result in premature protein termination (p.Trp1214*). This variant has been reported in individuals with autosomal dominant hypertrophic cardiomyopathy … (more)
The MYBPC3 c.3642G>A variant is predicted to result in premature protein termination (p.Trp1214*). This variant has been reported in individuals with autosomal dominant hypertrophic cardiomyopathy (Marsiglia et al. 2013. PubMed ID: 24093860; Table S1 in Helms et al. 2020. PubMed ID: 32841044; Table S2 in Burstein et al. 2021. PubMed ID: 32746448). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033131.5
First in ClinVar: Sep 16, 2023 Last updated: Apr 15, 2024 |
Comment:
MYBPC3: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
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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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Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. | Marsiglia JD | American heart journal | 2013 | PMID: 24093860 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. | Bashyam MD | Molecular and cellular biochemistry | 2012 | PMID: 21959974 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Text-mined citations for rs368765949 ...
HelpRecord last updated Apr 15, 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.