This missense variant replaces arginine with tryptophan at codon 724 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 29121657, 30645170). Two of these individuals carried a pathogenic variant in the same gene that could explain the observed phenotype. This variant has also been identified in 6/246748 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.
NM_000256.3(MYBPC3):c.2170C>T (p.Arg724Trp)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Uncertain significance
Uncertain significance (8)
Uncertain significance (8)
8 out of 9 submissions contributed to this classification
Help
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.
9
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.2170C>T (p.Arg724Trp)
Variation ID: 177901 Accession: VCV000177901.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47338658 (GRCh38) [ NCBI UCSC ] 11: 47360209 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 27, 2026 May 1, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.2170C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg724Trp missense NC_000011.10:g.47338658G>A NC_000011.9:g.47360209G>A NG_007667.1:g.19045C>T LRG_386:g.19045C>T LRG_386t1:c.2170C>T LRG_386p1:p.Arg724Trp - Protein change
- R724W
- Other names
- -
- Canonical SPDI
- NC_000011.10:47338657:G:A
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
| MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4727 | 4749 | |
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
Help
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
Feb 12, 2013 | RCV000154554.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2025 | RCV001039242.7 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2024 | RCV001182020.7 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2025 | RCV002223187.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 26, 2023 | RCV002426740.3 |
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. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Sep 02, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838945.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain Significance
(Nov 02, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004842385.1
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)
|
Comment:
show
This missense variant replaces arginine with tryptophan at codon 724 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 29121657, 30645170). Two of these individuals carried a pathogenic variant in the same gene that could explain the observed phenotype. This variant has also been identified in 6/246748 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 8
Zygosity: 8 Single Heterozygotes
|
|
|
Uncertain significance
(Jul 26, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV002731393.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
show
The p.R724W variant (also known as c.2170C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2170. The arginine at codon 724 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in patients with hypertrophic cardiomyopathy (HCM), including one proband in a study that tested ≥ 45 cardiomyopathy-associated genes (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:), and another in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 02;19:192-203). Two other studies identified the variant in HCM patients who each also carried a second MYBPC3 gene mutation (Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Jan 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202762.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 724 of the MYBPC3 protein (p.Arg724Trp). This variant is present in population databases (rs200399246, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 29121657, 33673806, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 177901). 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(May 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV006098583.9
First in ClinVar: Jun 22, 2025 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 10, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501381.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
Secondary finding: no
Platform type: NGS
|
|
|
Uncertain significance
(Jul 13, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199327.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(May 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347334.4
First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces arginine with tryptophan at codon 724 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 29121657, 30645170, 33673806, 33782553). Two of these individuals each carried different pathogenic variants in the MYBPC3 gene (PMID: 29121657, 30645170). This variant has been identified in 6/246748 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Uncertain significance
(Feb 12, 2013)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204227.3
First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 1
|
|
Comment:
Comment:
The p.R724W variant (also known as c.2170C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2170. The arginine at codon 724 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in patients with hypertrophic cardiomyopathy (HCM), including one proband in a study that tested ≥ 45 cardiomyopathy-associated genes (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:), and another in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 02;19:192-203). Two other studies identified the variant in HCM patients who each also carried a second MYBPC3 gene mutation (Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 724 of the MYBPC3 protein (p.Arg724Trp). This variant is present in population databases (rs200399246, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28790153, 29121657, 33673806, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 177901). 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.
Comment:
MYBPC3: PM2, PP3
Comment:
This missense variant replaces arginine with tryptophan at codon 724 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 29121657, 30645170, 33673806, 33782553). Two of these individuals each carried different pathogenic variants in the MYBPC3 gene (PMID: 29121657, 30645170). This variant has been identified in 6/246748 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.
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
| Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
| Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy. | Singer ES | Circulation. Genomic and precision medicine | 2019 | PMID: 30645170 |
| Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
| Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing. | Burns C | Circulation. Cardiovascular genetics | 2017 | PMID: 28790153 |
| 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 |
| 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 |
Text-mined citations for rs200399246 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jul 27, 2026
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.