ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3408C>A (p.Tyr1136Ter)
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.3408C>A (p.Tyr1136Ter)
Variation ID: 36611 Accession: VCV000036611.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332896 (GRCh38) [ NCBI UCSC ] 11: 47354447 (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 20, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3408C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Tyr1136Ter nonsense NC_000011.10:g.47332896G>T NC_000011.9:g.47354447G>T NG_007667.1:g.24807C>A LRG_386:g.24807C>A LRG_386t1:c.3408C>A LRG_386p1:p.Tyr1136Ter - Protein change
- Y1136*
- Other names
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- Canonical SPDI
- NC_000011.10:47332895:G: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.
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
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 |
3676 | 3695 |
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 (1) |
no assertion criteria provided
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May 26, 2015 | RCV000030289.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2020 | RCV000253851.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2022 | RCV000426587.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2023 | RCV000549683.12 |
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
(Jun 21, 2018)
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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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Blueprint Genetics
Accession: SCV000927757.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
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Pathogenic
(Dec 20, 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: SCV000515917.6
First in ClinVar: Mar 08, 2017 Last updated: Jan 07, 2023 |
Comment:
Reported in a two-month-old male with LVNC who also harbors the c.2373dupG variant in the MYPBC3 gene; Y1136X was inherited from his mother who has … (more)
Reported in a two-month-old male with LVNC who also harbors the c.2373dupG variant in the MYPBC3 gene; Y1136X was inherited from his mother who has a diagnosis of HCM, and c.2373dupG was inherited from his unaffected father (Haberer et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25262865, 24111713, 28408708, 34819141, 33673806, 27532257, 25611685) (less)
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Pathogenic
(Sep 21, 2011)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059237.5
First in ClinVar: May 03, 2013 Last updated: Oct 10, 2018 |
Comment:
The Tyr1136X variant leads to a premature stop at codon 1136, which is predicted to lead to a truncated or absent protein. Loss of function … (more)
The Tyr1136X variant leads to a premature stop at codon 1136, which is predicted to lead to a truncated or absent protein. Loss of function variants are an esta blished mechanism of disease for the MYBPC3 gene. Therefore, Tyr1136X variant me ets our criteria for pathogenicity (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 4
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Pathogenic
(Jan 06, 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: SCV000318293.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.Y1136* pathogenic mutation (also known as c.3408C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at … (more)
The p.Y1136* pathogenic mutation (also known as c.3408C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3408. This changes the amino acid from a tyrosine to a stop codon within coding exon 31. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203). This mutation was detected in trans with a second MYBPC3 mutation in an infant with non-compaction cardiomyopathy requiring heart transplant. The mother, who had only the p.Y1136* mutatiion, had a diagnosis of HCM (Haberer K et al. Can J Cardiol, 2014 Oct;30:1249.e1-3). 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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Pathogenic
(Nov 17, 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: SCV000623594.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr1136*) 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.Tyr1136*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 25262865, 27532257, 28408708). ClinVar contains an entry for this variant (Variation ID: 36611). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 2019)
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no assertion criteria provided
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: SCV001430862.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
The MYBPC3 Tyr1136Ter variant has been reported in a compound heterozygous infant born with an ventricular septal defect and LVNC, and a family history of … (more)
The MYBPC3 Tyr1136Ter variant has been reported in a compound heterozygous infant born with an ventricular septal defect and LVNC, and a family history of HCM on both sides of the family. The Tyr1136Ter segregated on it's own in the probands mother who had a diagnosis of HCM (Haberer K, et al., 2014). It has also been reported in 4 HCM probands (Alfares AA, et al., 2015; Walsh R, et al., 2017). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in a HCM proband and this variant was found to segregate to an affected family member (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been reported in at least two HCM probands (PS4_supporting), therefore we classify MYBPC3 Tyr1136Ter as "pathogenic". (less)
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Pathogenic
(May 26, 2015)
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no assertion criteria provided
Method: clinical testing
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Hypertrophic Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052956.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 31, 2015 |
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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 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
A case of an infant with compound heterozygous mutations for hypertrophic cardiomyopathy producing a phenotype of left ventricular noncompaction. | Haberer K | The Canadian journal of cardiology | 2014 | PMID: 25262865 |
Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Text-mined citations for rs193922383 ...
HelpRecord last updated Feb 28, 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.