ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1153G>A (p.Val385Met)
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.1153G>A (p.Val385Met)
Variation ID: 219403 Accession: VCV000219403.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47343562 (GRCh38) [ NCBI UCSC ] 11: 47365113 (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 Feb 2, 2016 May 1, 2024 Mar 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1153G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Val385Met missense NC_000011.10:g.47343562C>T NC_000011.9:g.47365113C>T NG_007667.1:g.14141G>A LRG_386:g.14141G>A LRG_386t1:c.1153G>A LRG_386p1:p.Val385Met - Protein change
- V385M
- Other names
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- Canonical SPDI
- NC_000011.10:47343561: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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 |
3941 | 3960 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000206400.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 12, 2023 | RCV001184019.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 26, 2021 | RCV002503799.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2022 | RCV002345726.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 7, 2024 | RCV003991469.1 |
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
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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: SCV000886819.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Uncertain significance
(Jul 26, 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: SCV002796999.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(May 12, 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: SCV001349890.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with methionine at codon 385 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). A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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
(Dec 31, 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: SCV000259253.7
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 385 of the MYBPC3 protein (p.Val385Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 385 of the MYBPC3 protein (p.Val385Met). This variant is present in population databases (rs772073491, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertropic cardiomyopathy (PMID: 21750094, 27532257, 31513939, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 219403). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
(Mar 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction 10
Affected status: yes
Allele origin:
unknown
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KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV004809099.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Number of individuals with the variant: 1
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Uncertain Significance
(Jan 11, 2024)
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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: SCV004834664.1
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 valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces valine with methionine at codon 385 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). A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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: 10
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Uncertain significance
(Jul 27, 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: SCV002623178.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.V385M variant (also known as c.1153G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide … (more)
The p.V385M variant (also known as c.1153G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1153. The valine at codon 385 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in various cardiomyopathy cohorts, including dilated cardiomyopathy cohorts and hypertrophic cardiomyopathy cohorts; however, clinical details were limited in some cases and additional alterations were identified in other cardiac-related genes (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Walsh R et al. Genet Med, 2017 02;19:192-203; Wang L et al. Compr Physiol, 2018 03;8:631-709; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Piriou N et al. ESC Heart Fail, 2020 May:[ePub ahead of print]; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has been reported in the Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 01, 2016)
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no assertion criteria provided
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: CSER - NEXT Medicine variant annotation
Accession: SCV000503534.1 First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
Comment:
Found in patient having exome sequencing for an unrelated indication. No known history of cardiomyopathy.
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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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Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy. | Suay-Corredera C | The Journal of biological chemistry | 2021 | PMID: 34097875 |
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation. | Thompson AD | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33782553 |
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. | Helms AS | Circulation. Genomic and precision medicine | 2020 | PMID: 32841044 |
Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies. | Piriou N | ESC heart failure | 2020 | PMID: 32356610 |
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
Thick Filament Protein Network, Functions, and Disease Association. | Wang L | Comprehensive Physiology | 2018 | PMID: 29687901 |
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 |
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. | Bick AG | American journal of human genetics | 2012 | PMID: 22958901 |
Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. | Waldmüller S | European journal of heart failure | 2011 | PMID: 21750094 |
Text-mined citations for rs772073491 ...
HelpRecord last updated May 08, 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.