This missense variant replaces arginine with glutamine at codon 1205 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has been identified in 6/279662 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.3614G>A (p.Arg1205Gln)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Uncertain significance
Uncertain significance (10)
Uncertain significance (10)
10 out of 10 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.
10
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.3614G>A (p.Arg1205Gln)
Variation ID: 181014 Accession: VCV000181014.37
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47332579 (GRCh38) [ NCBI UCSC ] 11: 47354130 (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 Mar 29, 2015 May 3, 2026 Mar 27, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.3614G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg1205Gln missense NC_000011.10:g.47332579C>T NC_000011.9:g.47354130C>T NG_007667.1:g.25124G>A LRG_386:g.25124G>A LRG_386t1:c.3614G>A LRG_386p1:p.Arg1205Gln - Protein change
- R1205Q
- Other names
-
p.R1205Q:CGG>CAG
- Canonical SPDI
- NC_000011.10:47332578:C:T
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
- 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 |
4724 | 4746 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 13, 2025 | RCV000158247.12 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 24, 2025 | RCV000168378.15 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 22, 2016 | RCV000449593.2 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2026 | RCV000618734.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 24, 2024 | RCV000777734.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 15, 2025 | RCV005861062.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 12, 2026 | RCV006688503.1 |
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. |
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
(Jun 10, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Blueprint Genetics
Accession: SCV000927289.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
|
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
(Apr 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000913692.5
First in ClinVar: May 20, 2019 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces arginine with glutamine at codon 1205 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has been identified in 6/279662 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
(Sep 05, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV000737301.7
First in ClinVar: Apr 14, 2018 Last updated: Oct 05, 2025 |
Comment:
show
The p.R1205Q variant (also known as c.3614G>A), located in coding exon 32 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3614. The arginine at codon 1205 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in one individual from a hypertrophic cardiomyopathy (HCM) testing cohort, but clinical details were not provided (Walsh R et al. Genet. Med., 2017 Feb;19:192-203); it has also been detected in a participant from the Framingham/Jackson Heart Study (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). This amino acid position is highly 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)
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
(Mar 12, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV007585612.1
First in ClinVar: May 03, 2026 Last updated: May 03, 2026 |
Comment:
show
Variant summary: MYBPC3 c.3614G>A (p.Arg1205Gln) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 2e-05 in 248278 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3614G>A has been observed in individual(s) affected with Cardiomyopathy (McGurk_2023, Thompson_2021, Walsh_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37652022, 33782553, 27532257). ClinVar contains an entry for this variant (Variation ID: 181014). Based on the evidence outlined above, the variant was classified as 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
(Jul 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004836579.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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 glutamine at codon 1205 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 hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has been identified in 6/279662 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: 10
Zygosity: 10 Single Heterozygotes
|
|
|
Uncertain significance
(Aug 22, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Peripheral neuropathy |
Claritas Genomics
Accession: SCV000537832.2
First in ClinVar: Mar 27, 2017 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Sex: female
|
|
|
Uncertain Significance
(Aug 15, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV006554667.1
First in ClinVar: Oct 12, 2025 Last updated: Oct 12, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Sudden cardiac death (present) , Sudden death (present) , Pulmonary embolism (present) , Cardiac arrhythmia (present)
|
|
|
Uncertain significance
(Nov 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000208182.19
First in ClinVar: Feb 24, 2015 Last updated: Nov 22, 2025 |
Comment:
show
Reported in the Framingham and Jackson Heart Study cohort in one individual without hypertrophy, and in another study in one individual with reported HCM without any clinical information provided (PMID: 22958901, 27532257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 33782553, 24793961, 22958901, 37652022) (less)
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
(Nov 24, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219069.11
First in ClinVar: Mar 29, 2015 Last updated: Feb 23, 2026 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1205 of the MYBPC3 protein (p.Arg1205Gln). This variant is present in population databases (rs730880596, gnomAD 0.006%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 181014). 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
(Mar 27, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV007541646.1
First in ClinVar: Apr 25, 2026 Last updated: Apr 25, 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
|
|
Comment:
Comment:
The p.R1205Q variant (also known as c.3614G>A), located in coding exon 32 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3614. The arginine at codon 1205 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in one individual from a hypertrophic cardiomyopathy (HCM) testing cohort, but clinical details were not provided (Walsh R et al. Genet. Med., 2017 Feb;19:192-203); it has also been detected in a participant from the Framingham/Jackson Heart Study (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). This amino acid position is highly 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.
Comment:
Variant summary: MYBPC3 c.3614G>A (p.Arg1205Gln) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 2e-05 in 248278 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3614G>A has been observed in individual(s) affected with Cardiomyopathy (McGurk_2023, Thompson_2021, Walsh_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37652022, 33782553, 27532257). ClinVar contains an entry for this variant (Variation ID: 181014). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This missense variant replaces arginine with glutamine at codon 1205 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 hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has been identified in 6/279662 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:
ACMG Criteria: PM2_P, PM5; Variant was found in heterozygous state.
Comment:
Reported in the Framingham and Jackson Heart Study cohort in one individual without hypertrophy, and in another study in one individual with reported HCM without any clinical information provided (PMID: 22958901, 27532257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 33782553, 24793961, 22958901, 37652022)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1205 of the MYBPC3 protein (p.Arg1205Gln). This variant is present in population databases (rs730880596, gnomAD 0.006%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 181014). 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:
PM2, PS4_supp, PM5_supp
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 |
| Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
| 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 |
| 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 |
| Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
| Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. | Bick AG | American journal of human genetics | 2012 | PMID: 22958901 |
Text-mined citations for rs730880596 ...
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 May 09, 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.