ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3811C>T (p.Arg1271Ter)
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.3811C>T (p.Arg1271Ter)
Variation ID: 42744 Accession: VCV000042744.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332075 (GRCh38) [ NCBI UCSC ] 11: 47353626 (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 May 29, 2016 Feb 20, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3811C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg1271Ter nonsense NC_000011.10:g.47332075G>A NC_000011.9:g.47353626G>A NG_007667.1:g.25628C>T LRG_386:g.25628C>T LRG_386t1:c.3811C>T LRG_386p1:p.Arg1271Ter - Protein change
- R1271*
- Other names
- p.R1271*:CGA>TGA
- Canonical SPDI
- NC_000011.10:47332074:G: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
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
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 |
3858 | 3875 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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) |
criteria provided, single submitter
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May 4, 2023 | RCV000158271.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 25, 2015 | RCV000208264.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000475268.12 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515345.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2022 | RCV000621330.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 5, 2018 | RCV000852435.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2023 | RCV001170942.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001807752.1 |
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
(Feb 25, 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: SCV000264044.2
First in ClinVar: Feb 27, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059270.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The p.Arg1271X variant in MYBPC3 gene has been identified in 6 individuals with HCM and segregated with disease in 1 affected family member (Olivotto 2008, … (more)
The p.Arg1271X variant in MYBPC3 gene has been identified in 6 individuals with HCM and segregated with disease in 1 affected family member (Olivotto 2008, Marston 2009, Lopes 2013, Walsh 2017, LMM data). It was also identified in 1 individual with early onset DCM who carried an additional pathogenic variant in MYBCP3 (LMM data). It has been identified in 2/246124 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42744). This nonsense variant leads to a premature termination codon at position 1271, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBCP3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. (less)
Number of individuals with the variant: 3
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Pathogenic
(Mar 22, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333593.3
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
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Pathogenic
(May 18, 2017)
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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: SCV000611211.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(Jun 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Long QT Syndrome
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995120.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 03, 2022)
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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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3billion
Accession: SCV002058836.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042744, PMID:18533079). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Pathogenic
(Jan 17, 2022)
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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: SCV002074311.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant summary: MYBPC3 c.3811C>T (p.Arg1271X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MYBPC3 c.3811C>T (p.Arg1271X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with hypertrophic cardiomyopathy in HGMD and have been cited as pathogenic in ClinVar. The variant allele was found at a frequency of 8.1e-06 in 246124 control chromosomes (gnomAD). c.3811C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (examples: Martson_2009, Coppini_2014, Ho_2018, Hathaway_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated absence of the expected truncated protein and significantly lower quantity of MyBP-C in myofibrils compared with non-failing donor heart muscle, as determined in myectomy sample(s) with the variant (Martson_2009). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=6) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 26, 2022)
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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: SCV000740206.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R1271* pathogenic mutation (also known as c.3811C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at … (more)
The p.R1271* pathogenic mutation (also known as c.3811C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3811. This changes the amino acid from an arginine to a stop codon within coding exon 33. This alteration occurs at the 3' terminus of theMYBPC3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 4 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Marston S et al. Circ. Res., 2009 Jul;105:219-22; Judge DP. JAMA, 2009 Dec;302:2471-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 04, 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: SCV000208206.16
First in ClinVar: Feb 24, 2015 Last updated: Jun 03, 2023 |
Comment:
Identified in individuals with HCM referred for genetic testing at GeneDx and in published literature (Olivotto et al., 2008; Lopes et al., 2013; Arbustini et … (more)
Identified in individuals with HCM referred for genetic testing at GeneDx and in published literature (Olivotto et al., 2008; Lopes et al., 2013; Arbustini et al., 2017; Walsh et al., 2017; Ho et al., 2018; Bonaventura et al., 2019); Reported in one patient with early onset familial DCM requiring heart transplantation at age 3, who also harbored the p.(Q404*) variant in trans (Judge et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 4 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Functional studies demonstrate a damaging effect with reduced MYBPC3 protein in a myomectomy sample from an individual with this variant (Marston et al., 2009); This variant is associated with the following publications: (PMID: 23396983, 25524337, 25525159, 18533079, 30297972, 27532257, 28254189, 31110529, 31589614, 33673806, 19574547, 25351510, 33087929, 33996946, 34076677, 35626289, 19996403) (less)
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Pathogenic
(Nov 29, 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: SCV004358619.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 33 of the major myosin binding region of the MYBPC3 gene, creating a premature translation stop signal in … (more)
This variant changes 1 nucleotide in exon 33 of the major myosin binding region of the MYBPC3 gene, creating a premature translation stop signal in the C-terminus region. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using myomectomy samples from a carrier individual have shown reduced protein expression levels (PMID: 19574547). This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 19574547, 23396983, 25524337, 27532257, 30297972, 31110529, 33495596; communication with external laboratories: ClinVar SCV000208206.13, SCV000059270.6). It has also been reported in one individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806), in one individual affected with cardiomyopathy (PMID: 28254189), and in homozygous state in one child affected with hypertrophic cardiomyopathy (DOI:10.32592/psj.21.3.194). A splicing variant occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 42746). This variant has been identified in 2/246124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 24, 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: SCV000546415.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1271*) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg1271*) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs397516042, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 23396983, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 42744). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic. (less)
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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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Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy. | Bonaventura J | Archives of medical science : AMS | 2019 | PMID: 31110529 |
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
Reply: A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation. | Arbustini E | Journal of the American College of Cardiology | 2017 | PMID: 28254189 |
Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data. | Alejandra Restrepo-Cordoba M | Journal of cardiovascular translational research | 2017 | PMID: 28138913 |
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 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
Use of genetics in the clinical evaluation of cardiomyopathy. | Judge DP | JAMA | 2009 | PMID: 19996403 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
[Adenosine triphosphatase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase activity of pancreas of thyroidectomized rats]. | Tsapok PI | Ukrainskii biokhimicheskii zhurnal (1978) | 1978 | PMID: 208206 |
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Text-mined citations for rs397516042 ...
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.