VCV000042686.23 - ClinVar

NM_000256.3(MYBPC3):c.3098G>A (p.Arg1033Gln)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (11)

11 out of 11 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.3098G>A (p.Arg1033Gln)

Variation ID: 42686 Accession: VCV000042686.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47333649 (GRCh38) [ NCBI UCSC ] 11: 47355200 (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	Jun 1, 2016	Aug 4, 2026	Jan 5, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3098G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg1033Gln	missense
NC_000011.10:g.47333649C>T
NC_000011.9:g.47355200C>T
NG_007667.1:g.24054G>A
LRG_386:g.24054G>A
LRG_386t1:c.3098G>A	LRG_386p1:p.Arg1033Gln

... more HGVS ... less HGVS

Protein change

R1033Q

Other names

p.R1033Q:CGG>CAG

Canonical SPDI

NC_000011.10:47333648:C:T

Global minor allele frequency (GMAF) Help The 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), exomes 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA013470 dbSNP: rs397516003 VarSome

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
Gene	OMIM	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	4728	4750

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.
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 29, 2019	RCV000035559.7
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 5, 2026	RCV000768512.12
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Feb 24, 2022	RCV002490478.1
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Mar 16, 2022	RCV001798085.3
Hypertrophic cardiomyopathy 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 4, 2025	RCV003988824.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2019	RCV004017293.1
not provided	Uncertain significance (1)	criteria provided, single submitter	May 31, 2013	RCV006741091.1

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 (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Center for Human Genetics, University of Leuven Accession: SCV000886824.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019	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 (Feb 24, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002784484.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Dec 23, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004849150.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: show The c.3098G>A (p.R1033Q) alteration is located in exon 29 (coding exon 29) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 3098, causing the arginine (R) at amino acid position 1033 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, 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 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004836660.2 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)	Publications: PubMed (6) PubMed: 27532257‚ 28679633‚ 29121657‚ 31513939‚ 33658040‚ 33782553 Comment: show This missense variant replaces arginine with glutamine at codon 1033 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). Splice site prediction tools indicate that this variant may activate a novel acceptor site, however a functional RNA minigene assay showed inconclusive splice effects (PMID: 28679633). This variant has been reported in at individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 29121657, 31513939, 33658040, 33782553; Chung 2018, dissertation, Yonsei University). This variant has been identified in 2/246292 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 more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 3 Zygosity: 2 Homozygotes, 1 Single Heterozygote

Uncertain significance (Apr 25, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not specified	GeneDx Accession: SCV000208391.10 First in ClinVar: Feb 24, 2015 Last updated: Jun 01, 2016	Comment: show A variant of uncertain significance has been identified in the MYBPC3 gene. The Arg1033Gln (R1033Q) variant variant has been previously reported in association with DCM (Zimmerman et al., 2010), however, clinical details regarding the patient, or the patient cohort where this variant was identified, were not described. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1033Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while a missense variant in the same residue (R1033Q) in nearby residues (T1028I, T1028S, R1036C, R1037C) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. (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 (Aug 29, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059209.5 First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020	Publications: PubMed (4) PubMed: 20474083‚ 27532257‚ 28679633‚ 29121657 Comment: show The p.Arg1033Gln variant in MYBPC3 has been identified in 2 individuals with HCM (Viswanathan 2017, LMM data). It was also identified in 2/246292 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID#42686). Computational tools suggest that this variant may impact protein function; however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Uncertain significance (Mar 16, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002042191.2 First in ClinVar: Dec 29, 2021 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868 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 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004805456.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Uncertain significance (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV006583800.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Publications: PubMed (2) PubMed: 20474083‚ 23283745 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.46 (>=0.2, moderate evidence for spliceogenicity)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 20474083). A different missense change at the same codon (p.Arg1033Trp) has been reported to be associated with MYBPC3-related disorder (PMID: 23283745). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Method: exome sequencing

Uncertain significance (Jan 05, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000936427.6 First in ClinVar: Aug 13, 2019 Last updated: Feb 15, 2026	Publications: PubMed (8) PubMed: 27532257‚ 28679633‚ 29121657‚ 31513939‚ 33658040‚ 33782553‚ 35626289‚ 37652022 Comment: show This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1033 of the MYBPC3 protein (p.Arg1033Gln). This variant is present in population databases (rs397516003, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28679633, 29121657, 31513939, 33658040, 33782553, 35626289, 37652022). ClinVar contains an entry for this variant (Variation ID: 42686). 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 31, 2013) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280256.2 First in ClinVar: Jun 01, 2016 Last updated: Aug 04, 2026	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown

Comment:

The c.3098G>A (p.R1033Q) alteration is located in exon 29 (coding exon 29) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 3098, causing the arginine (R) at amino acid position 1033 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces arginine with glutamine at codon 1033 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). Splice site prediction tools indicate that this variant may activate a novel acceptor site, however a functional RNA minigene assay showed inconclusive splice effects (PMID: 28679633). This variant has been reported in at individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 29121657, 31513939, 33658040, 33782553; Chung 2018, dissertation, Yonsei University). This variant has been identified in 2/246292 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:

A variant of uncertain significance has been identified in the MYBPC3 gene. The Arg1033Gln (R1033Q) variant variant has been previously reported in association with DCM (Zimmerman et al., 2010), however, clinical details regarding the patient, or the patient cohort where this variant was identified, were not described. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1033Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while a missense variant in the same residue (R1033Q) in nearby residues (T1028I, T1028S, R1036C, R1037C) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined.

Comment:

The p.Arg1033Gln variant in MYBPC3 has been identified in 2 individuals with HCM (Viswanathan 2017, LMM data). It was also identified in 2/246292 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID#42686). Computational tools suggest that this variant may impact protein function; however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.46 (>=0.2, moderate evidence for spliceogenicity)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 20474083). A different missense change at the same codon (p.Arg1033Trp) has been reported to be associated with MYBPC3-related disorder (PMID: 23283745). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1033 of the MYBPC3 protein (p.Arg1033Gln). This variant is present in population databases (rs397516003, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 28679633, 29121657, 31513939, 33658040, 33782553, 35626289, 37652022). ClinVar contains an entry for this variant (Variation ID: 42686). 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.

Citations for germline classification of this variant

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
The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes.	Sepp R	Diagnostics (Basel, Switzerland)	2022	PMID: 35626289
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
Effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in patients with hypertrophic cardiomyopathy.	Chung H	Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance	2021	PMID: 33658040
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.	Viswanathan SK	PloS one	2017	PMID: 29121657
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.	Ito K	Proceedings of the National Academy of Sciences of the United States of America	2017	PMID: 28679633
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
Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy.	Zou Y	Molecular biology reports	2013	PMID: 23283745
A novel custom resequencing array for dilated cardiomyopathy.	Zimmerman RS	Genetics in medicine : official journal of the American College of Medical Genetics	2010	PMID: 20474083
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Text-mined citations for rs397516003 ...

These 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 Aug 04, 2026