ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.50G>A (p.Arg17Gln)
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.50G>A (p.Arg17Gln)
Variation ID: 164160 Accession: VCV000164160.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47351481 (GRCh38) [ NCBI UCSC ] 11: 47373032 (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 7, 2017 May 7, 2024 Mar 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.50G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg17Gln missense NC_000011.10:g.47351481C>T NC_000011.9:g.47373032C>T NG_007667.1:g.6222G>A LRG_386:g.6222G>A LRG_386t1:c.50G>A LRG_386p1:p.Arg17Gln - Protein change
- R17Q
- Other names
- p.R17Q:CGG>CAG
- Canonical SPDI
- NC_000011.10:47351480: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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00023
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 |
3892 | 3909 |
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 11, 2024 | RCV000151174.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 21, 2024 | RCV000619032.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV000701754.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2020 | RCV000766303.6 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 13, 2023 | RCV000777988.8 |
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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Uncertain significance
(Mar 07, 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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GeneDx
Accession: SCV000208113.10
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
The R17Q variant of uncertain significance in the MYBPC3 gene has previously been reported in one patient with HCM with no family history of the … (more)
The R17Q variant of uncertain significance in the MYBPC3 gene has previously been reported in one patient with HCM with no family history of the disease, but was also present in 1/200 healthy control individuals (Garcia-Castro et al., 2008). This variant has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant is observed in 9/32876 (0.03%) alleles from individuals of Latino ancestry and in 9/105042 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the R17Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. (less)
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Uncertain significance
(May 01, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198992.4
First in ClinVar: Feb 02, 2015 Last updated: Jan 07, 2017 |
Comment:
The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the … (more)
The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. At this time, additional information is needed to fully asses s the clinical significance of this variant. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jul 10, 2020)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714975.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 17, 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: SCV002042220.2
First in ClinVar: Dec 29, 2021 Last updated: Mar 11, 2023 |
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Uncertain significance
(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: SCV000830569.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the MYBPC3 protein (p.Arg17Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the MYBPC3 protein (p.Arg17Gln). This variant is present in population databases (rs374630007, gnomAD 0.03%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25342278, 29121657, 30871747; Invitae). ClinVar contains an entry for this variant (Variation ID: 164160). 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
(Feb 05, 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: SCV004845008.1
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 arginine with glutamine at codon 17 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with glutamine at codon 17 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 over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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: 30
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Uncertain significance
(Oct 13, 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: SCV000914094.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 17 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with glutamine at codon 17 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 over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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
(Feb 21, 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: SCV000740010.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R17Q variant (also known as c.50G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide … (more)
The p.R17Q variant (also known as c.50G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 50. The arginine at codon 17 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Alfares AA et al. Genet Med. 2015 Nov;17(11):880-8; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139; Helms AS at al. Circ Genom Precis Med. 2020 Oct;13(5):396-405). This variant was detected in both affected and unaffected relatives in a family with HCM (Dias GM et al. Circ Genom Precis Med. 2021 Oct;14(5):e003476). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039538.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
Variant summary: MYBPC3 c.50G>A (p.Arg17Gln) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of … (more)
Variant summary: MYBPC3 c.50G>A (p.Arg17Gln) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 235814 control chromosomes. The observed variant frequency is approximately 2.71 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.50G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 164160). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (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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The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. | McGurk KA | American journal of human genetics | 2023 | PMID: 37652022 |
MYH7 p.Glu903Gln Is a Pathogenic Variant Associated With Hypertrophic Cardiomyopathy. | Dias GM | Circulation. Genomic and precision medicine | 2021 | PMID: 34555931 |
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 |
Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants. | Pottinger TD | Journal of the American Heart Association | 2020 | PMID: 32009526 |
Molecular characterization of Portuguese patients with dilated cardiomyopathy. | Sousa A | Revista portuguesa de cardiologia | 2019 | PMID: 30871747 |
Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. | Ochoa JP | Journal of the American College of Cardiology | 2018 | PMID: 30442288 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. | Mademont-Soler I | PloS one | 2017 | PMID: 28771489 |
Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. | Gómez J | Circulation. Cardiovascular genetics | 2017 | PMID: 28356264 |
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 |
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 |
Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing. | Gómez J | Circulation journal : official journal of the Japanese Circulation Society | 2014 | PMID: 25342278 |
[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. | García-Castro M | Revista espanola de cardiologia | 2009 | PMID: 19150014 |
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Text-mined citations for rs374630007 ...
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.