ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.836G>C (p.Gly279Ala)
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.836G>C (p.Gly279Ala)
Variation ID: 42798 Accession: VCV000042798.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47347666 (GRCh38) [ NCBI UCSC ] 11: 47369217 (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 Dec 6, 2014 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.836G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Gly279Ala missense NC_000011.10:g.47347666C>G NC_000011.9:g.47369217C>G NG_007667.1:g.10037G>C LRG_386:g.10037G>C LRG_386t1:c.836G>C LRG_386p1:p.Gly279Ala Q14896:p.Gly279Ala - Protein change
- G279A
- Other names
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- Canonical SPDI
- NC_000011.10:47347665:C:G
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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.
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
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
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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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Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000035674.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 28, 2012 | RCV000154166.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 21, 2022 | RCV001170205.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2023 | RCV000628836.8 | |
Uncertain significance (3) |
criteria provided, single submitter
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May 3, 2019 | RCV001698950.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV002433494.2 |
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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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: SCV000886817.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Uncertain significance
(Aug 09, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001332757.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
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Uncertain significance
(Oct 18, 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: SCV000749743.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 279 of the MYBPC3 protein (p.Gly279Ala). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 279 of the MYBPC3 protein (p.Gly279Ala). This variant is present in population databases (rs375774648, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 30731207, 30871747, 31513939). ClinVar contains an entry for this variant (Variation ID: 42798). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
(Nov 21, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001345867.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with alanine at codon 279 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with alanine at codon 279 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747), at least one individual affected with hypertrophic cardiomyopathy (PMID: 31513939, 33495597; Lopes 2020), and one case of sudden cardiac death (PMID: 31376648). This variant has also been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503) and left ventricular outflow tract obstruction (PMID: 25127965), both of whom carried a known pathogenic variant in the same gene that could explain the observed phenotype. This variant has been identified in 7/218120 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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Uncertain Significance
(Nov 20, 2023)
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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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All of Us Research Program, National Institutes of Health
Accession: SCV004834715.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces glycine with alanine at codon 279 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with alanine at codon 279 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30871747), at least one individual affected with hypertrophic cardiomyopathy (PMID: 31513939, 33495597; Lopes 2020), and one case of sudden cardiac death (PMID: 31376648). This variant has also been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503) and left ventricular outflow tract obstruction (PMID: 25127965), both of whom carried a known pathogenic variant in the same gene that could explain the observed phenotype. This variant has been identified in 7/218120 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)
Number of individuals with the variant: 7
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Uncertain Significance
(May 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059325.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
This variant has been seen in one patient with HCM (Richard 2003). It's also been reported in an individual who had this and 2 additional … (more)
This variant has been seen in one patient with HCM (Richard 2003). It's also been reported in an individual who had this and 2 additional MYBPC3 variants in cis (p.Glu441Lys, p.Gln76Ter) and also a variant in MYH7 (p.Ile1927Phe) (Millat 2010). The variant has also been reported in two affected siblings compound heterozygous for this variant and the MYBPC3 Glu258Lys variant, each from one possibly mildly affected parent (Lopes 2014). The variant is in gnomAD at 0.005% (5 alleles) and classified in ClinVar with 2 stars as VUS by CHEO, Stanford, and CSER. In summary, this variant is of uncertain significance but we would lean towards a more likely benign impact. (less)
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Uncertain significance
(Jan 26, 2024)
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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: SCV002678727.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G279A variant (also known as c.836G>C), located in coding exon 8 of the MYBPC3 gene, results from a G to C substitution at nucleotide … (more)
The p.G279A variant (also known as c.836G>C), located in coding exon 8 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 836. The glycine at codon 279 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Richard P et al. Circulation, 2003 May;107:2227-32; Millat G et al. Eur J Med Genet, 2010 Jul;53:261-7; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has also been described in dilated cardiomyopathy (DCM), left ventricular outflow tract obstruction, and drug-induced sudden unexplained death cohorts (Lopes LR et al. Int J Cardiol, 2014 Oct;176:1264-7; Cardoso B et al. Rev Port Cardiol, 2017 Mar;36:155-165; Martinez-Matilla M et al. Forensic Sci Int Genet, 2019 09;42:203-212; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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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: SCV001958399.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, hypertrophic
(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: SCV000190409.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Uncertain significance
(Mar 28, 2012)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280283.2
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly279Ala Based on the data reviewed, we classify this variant as a variant of uncertain significance. This variant has been reported in 2 presumably unrelated individuals with HCM. Richard et al (2003) identified p.Gly279Ala in one individual with HCM who had no other variants in the nine sarcomere genes analyzed. Millat et al. (2010) reported one individual with HCM who had three variants on one MYBPC3 allele (p.Glu441Lys, p.Gln76Ter, p.Gly279Ala) and also had an additional variant in MYH7 (p.Ile1927Phe). Unfortunately age of onset and severity were not reported. There is no segregation data available for p.Gly279Ala. p.Gly279Ala is located in a conserved region of the MYBPC3 gene coding for the linker 1-2 region of the protein. However, p.Gly279Ala results in a conservative amino acid substitution and an Alanine is present at codon 279 in rodent. Variants in nearby codons (p.Arg273His, p.Gly278Glu, p.Arg282Trp) have been reported in association with HCM. This variant was not identified in 100 control individuals by Richard et al. This variant was not listed in dbSNP, 1000 genomes, or the NHLBI exome project database. (less)
Number of individuals with the variant: 3
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Uncertain significance
(-)
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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: SCV001926195.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 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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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths. | Martinez-Matilla M | Forensic science international. Genetics | 2019 | PMID: 31376648 |
Molecular characterization of Portuguese patients with dilated cardiomyopathy. | Sousa A | Revista portuguesa de cardiologia | 2019 | PMID: 30871747 |
Genetic Diagnostic Testing for Inherited Cardiomyopathies: Considerations for Offering Multi-Gene Tests in a Health Care Setting. | Daoud H | The Journal of molecular diagnostics : JMD | 2019 | PMID: 30731207 |
Clinical and genetic diagnosis of familial hypertrophic cardiomyopathy: Results in pediatric cardiology. | Cardoso B | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2017 | PMID: 28214152 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Left ventricular outflow tract obstruction as a primary phenotypic expression of hypertrophic cardiomyopathy in mutation carriers without hypertrophy. | Lopes LR | International journal of cardiology | 2014 | PMID: 25127965 |
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 |
Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy. | Millat G | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20800588 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
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Text-mined citations for rs375774648 ...
HelpRecord last updated May 01, 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.