VCV000042735.72 - ClinVar

NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (25); Likely pathogenic (1)

26 out of 30 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.3697C>T (p.Gln1233Ter)

Variation ID: 42735 Accession: VCV000042735.72

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332189 (GRCh38) [ NCBI UCSC ] 11: 47353740 (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	Jul 8, 2016	Jul 27, 2026	Jan 27, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3697C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gln1233Ter	nonsense
NC_000011.10:g.47332189G>A
NC_000011.9:g.47353740G>A
NG_007667.1:g.25514C>T
LRG_386:g.25514C>T
LRG_386t1:c.3697C>T	LRG_386p1:p.Gln1233Ter

... more HGVS ... less HGVS

Protein change

Q1233*

Other names

p.Q1233*:CAG>TAG
p.Gln1233*

Canonical SPDI

NC_000011.10:47332188:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA014648 dbSNP: rs397516037 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	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.
Hypertrophic cardiomyopathy 4	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Dec 23, 2025	RCV000035610.19
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 16, 2025	RCV000158254.35
Hypertrophic cardiomyopathy	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 27, 2026	RCV000168193.24
Primary familial hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 22, 2025	RCV000208463.5
Cardiovascular phenotype	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 5, 2024	RCV000588073.4
Left ventricular hypertrophy	Pathogenic (1)	no assertion criteria provided	Aug 28, 2017	RCV000678715.2
Cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 22, 2024	RCV001188335.8
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 10, 2020	RCV001270363.3
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Pathogenic (1)	criteria provided, single submitter	Aug 6, 2021	RCV002482961.2
Dilated cardiomyopathy 1I	Pathogenic (1)	criteria provided, single submitter	Sep 26, 2023	RCV003390723.1

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.
Pathogenic (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: SCV000886773.1 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

Pathogenic (Nov 17, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002103237.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (6) PubMed: 30025578‚ 30550750‚ 30847666‚ 31513939‚ 31737537‚ 33673806 Comment: show PP1, PM2, PS4, PVS1 (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

Pathogenic (Apr 19, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002042207.2 First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 27, 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: SCV004836570.2 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 (17) PubMed: 11499719‚ 18957093‚ 21985754‚ 24510615‚ 25031304‚ 25351510‚ 27532257‚ 27600940‚ 28615295‚ 33495596‚ 33495597‚ 33673806‚ 34542152‚ 34598319‚ 35176171‚ 38002985‚ 38540378 Comment: show This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 25 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295, 33495596, 33495597, 33673806, 34542152, 34598319, 35176171, 38002985, 38540378). This variant has been identified in 2/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (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: 2 Zygosity: 2 Single Heterozygotes

Pathogenic (Dec 10, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	see cases (Autosomal dominant inheritance)	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations Accession: SCV001450505.2 First in ClinVar: Dec 16, 2020 Last updated: Apr 13, 2025	Comment: show We observed the genetic variant c.3697C>T (p.Q1233) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233) variant to be pathogenic. (less) Observation: 4 Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Left ventricular noncompaction cardiomyopathy (present) , Hypertrophic cardiomyopathy (present) , Supraventricular arrhythmia (present) , Atrial fibrillation (present) Zygosity: 1 Single Heterozygote Age: 30-39 years Sex: female Observation 2 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Hypertrophic cardiomyopathy (present) , Left ventricular noncompaction cardiomyopathy (present) , Abnormal mitral valve physiology (present) , Premature ventricular contraction (present) , Cardiac arrhythmia (present) Zygosity: 1 Single Heterozygote Age: 30-39 years Sex: female Comment on evidence: The p.Q1233* variant in proband K. was observed along with the variant p.E739K in MYBPC3 gene, also heterozygous. The family was unavailable for analysis. Observation 3 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Left ventricular noncompaction cardiomyopathy (present) , Hypertrophic cardiomyopathy (present) , Atrial fibrillation (present) Comment on clinical features: There were several cases of SCD in the proband's family. Zygosity: 1 Single Heterozygote Age: 30-39 years Sex: male Observation 4 Collection method: clinical testing Allele origin: unknown Affected status: yes Clinical Features: Left ventricular noncompaction cardiomyopathy (present) , Ventricular tachycardia (present) , Ventricular fibrillation (present) , Arrhythmogenic Right Ventricular Dysplasia (present) Zygosity: 1 Single Heterozygote Age: 60-69 years Sex: female Comment on evidence: The p.Q1233* variant in the proband I. was observed along with variant p.R237W in MYH7 gene.

Pathogenic (Jun 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiovascular phenotype	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV006070399.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Comment: show PVS1, PS4, PP1_strong, PM2, PP5 (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

Pathogenic (Feb 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratory of Genetics, Children's Clinical University Hospital Latvia Accession: SCV006109827.1 First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 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

Pathogenic (Dec 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Primary familial hypertrophic cardiomyopathy	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations Accession: SCV007126649.1 First in ClinVar: Dec 27, 2025 Last updated: Dec 27, 2025	Comment: show Heterozygous variant NM_000256.3:c.3697C>T (p.Gln1233Ter) in the MYBPC3 gene was found in a proband (Age: 35, male, Caucasian) diagnosed with (C0949658). The variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total 8.675e-06. (Date of access 2025-12-22). In accordance with ACMG (2015) criteria this variant is classified as Pathogenic with following criteria selected: PM2, PVS1, PP1_Strong, PS4_Strong. (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 Number of individuals with the variant: 1

Pathogenic (Nov 04, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Variant Classification)	Primary familial hypertrophic cardiomyopathy	Blueprint Genetics Accession: SCV000264042.2 First in ClinVar: Feb 27, 2016 Last updated: Sep 22, 2018	Publications: PubMed (5) PubMed: 11499719‚ 16199542‚ 18409188‚ 18957093‚ 21985754 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 Number of individuals with the variant: 1

Pathogenic (Jun 06, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Cardiovascular phenotype	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696331.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (9) PubMed: 11499719‚ 12974739‚ 15519027‚ 16199542‚ 16715312‚ 18403758‚ 18409188‚ 18957093‚ 24510615 Comment: show Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (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

Pathogenic (Jul 17, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428646.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	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 Number of individuals with the variant: 1

Pathogenic (Mar 24, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV001984989.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: show PVS1, PS4, PP5, PP1 (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

Pathogenic (Aug 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health Accession: SCV002522188.2 First in ClinVar: Jun 03, 2022 Last updated: Oct 07, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Sep 09, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000737358.4 First in ClinVar: Mar 17, 2018 Last updated: Nov 29, 2022	Publications: PubMed (24) PubMed: 11499719‚ 15519027‚ 16199542‚ 16715312‚ 18409188‚ 18957093‚ 21409595‚ 21985754‚ 22455086‚ 24510615‚ 25031304‚ 25892673‚ 26271555‚ 27532257‚ 27600940‚ 28408708‚ 28615295‚ 29121657‚ 30025578‚ 30550750‚ 30847666‚ 31513939‚ 31737537‚ 33673806 Comment: show The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (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

Pathogenic (Mar 31, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758620.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: show ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3 (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

Pathogenic (Aug 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002775432.1 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

Pathogenic (Nov 14, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208189.12 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: show Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806) (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

Pathogenic (Sep 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dilated cardiomyopathy 1I	KardioGenetik, Herz- und Diabeteszentrum NRW Accession: SCV004101821.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

Pathogenic (Apr 05, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059261.6 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 11499719‚ 15519027‚ 16199542‚ 16715312‚ 18957093 Comment: show The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. (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

Likely pathogenic (Jul 30, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Center of Genomic medicine, Geneva, University Hospital of Geneva Study: Final Reports_Cases2015_1 Accession: SCV000292232.2 First in ClinVar: Jul 08, 2016 Last updated: Apr 13, 2025	Comment: show This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy. (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 Age: 60-70 years Sex: female

Pathogenic (Apr 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001355372.3 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (17) PubMed: 11499719‚ 18957093‚ 21985754‚ 24510615‚ 25031304‚ 25351510‚ 27532257‚ 27600940‚ 28615295‚ 33495596‚ 33495597‚ 33673806‚ 34542152‚ 34598319‚ 35176171‚ 38002985‚ 38540378 Comment: show This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 25 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295, 33495596, 33495597, 33673806, 34542152, 34598319, 35176171, 38002985, 38540378). This variant has been identified in 2/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (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 Platform type: NGS

Pathogenic (May 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Institute of Immunology and Genetics Kaiserslautern Accession: SCV006305996.1 First in ClinVar: Aug 16, 2025 Last updated: Aug 16, 2025	Comment: show ACMG Criteria: PVS1, PS4_M, PM2_P, PP1_M, PP5; Variant was found in heterozygous state. (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 Clinical Features: Hypertrophic cardiomyopathy (present)

Pathogenic (Feb 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Classification criteria August 2017)	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance)	Institute of Human Genetics Munich, TUM University Hospital Accession: SCV006302622.5 First in ClinVar: Aug 03, 2025 Last updated: Sep 22, 2025	Publications: PubMed (1) PubMed: 11499719 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 Number of individuals with the variant: 1 Clinical Features: Hypertrophic cardiomyopathy (present)

Pathogenic (Jan 27, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000218858.14 First in ClinVar: Mar 29, 2015 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 11499719‚ 18957093‚ 19574547‚ 21985754‚ 28492532 Comment: show This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (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

Pathogenic (Dec 23, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV007538055.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Publications: PubMed (1) PubMed: 32841044 Comment: show This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is present in gnomAD <0.01 (v4: 14 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar. Additional information: This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Jun 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV005050617.18 First in ClinVar: Jun 17, 2024 Last updated: Jul 27, 2026	Comment: show MYBPC3: PVS1, PP1:Strong, PS4:Moderate, PM2:Supporting, PP4 (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 Number of individuals with the variant: 3

Pathogenic (Aug 28, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Left ventricular hypertrophy	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000804884.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001920537.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001952191.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 21, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 19, 2024) N Not contributing to aggregate classification	no assertion criteria provided	Hypertrophic cardiomyopathy 4	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV006323746.1 First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 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

Comment:

This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 25 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295, 33495596, 33495597, 33673806, 34542152, 34598319, 35176171, 38002985, 38540378). This variant has been identified in 2/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic.

Comment:

Heterozygous variant NM_000256.3:c.3697C>T (p.Gln1233Ter) in the MYBPC3 gene was found in a proband (Age: 35, male, Caucasian) diagnosed with (C0949658). The variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total 8.675e-06. (Date of access 2025-12-22). In accordance with ACMG (2015) criteria this variant is classified as Pathogenic with following criteria selected: PM2, PVS1, PP1_Strong, PS4_Strong.

Comment:

Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806)

Comment:

The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner.

Comment:

This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is present in gnomAD <0.01 (v4: 14 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar. Additional information: This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Massive Parallel DNA Sequencing of Patients with Inherited Cardiomyopathies in Cyprus and Suggestion of Digenic or Oligogenic Inheritance.	Koutsofti C	Genes	2024	PMID: 38540378
Hypertrophic Cardiomyopathy in Underrepresented Populations: Clinical and Genetic Landscape Based on a Russian Single-Center Cohort Study.	Chumakova OS	Genes	2023	PMID: 38002985
Genotype-phenotype correlations in Polish patients with hypertrophic cardiomyopathy: Preliminary report.	Osadnik T	Kardiologia polska	2022	PMID: 35176171
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.	Park J	Human molecular genetics	2022	PMID: 34542152
Targeted exome analysis of Russian patients with hypertrophic cardiomyopathy.	Filatova EV	Molecular genetics & genomic medicine	2021	PMID: 34598319
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.	Tadros R	Nature genetics	2021	PMID: 33495596
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
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.	Marschall C	Cardiovascular diagnosis and therapy	2019	PMID: 31737537
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
MYBPC3 truncation mutations enhance actomyosin contractile mechanics in human hypertrophic cardiomyopathy.	O'Leary TS	Journal of molecular and cellular cardiology	2019	PMID: 30550750
Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.	Bagnall RD	Journal of the American College of Cardiology	2018	PMID: 30025578
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.	Viswanathan SK	PloS one	2017	PMID: 29121657
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy.	Ross SB	Circulation. Cardiovascular genetics	2017	PMID: 28615295
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications.	Ingles J	Circulation. Cardiovascular genetics	2017	PMID: 28408708
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
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
Clinical application of WHF-MOGE(S) classification for hypertrophic cardiomyopathy.	Agarwal A	Global heart	2015	PMID: 26271555
Targeted next-generation sequencing (NGS) of nine candidate genes with custom AmpliSeq in patients and a cardiomyopathy risk group.	Glotov AS	Clinica chimica acta; international journal of clinical chemistry	2015	PMID: 25892673
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy.	Helms AS	Circulation. Cardiovascular genetics	2014	PMID: 25031304
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615
Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy.	Curila K	Acta cardiologica	2012	PMID: 22455086
The Gln1233ter mutation of the myosin binding protein C gene: causative mutation or innocent polymorphism in patients with hypertrophic cardiomyopathy?	Tóth T	International journal of cardiology	2011	PMID: 21985754
A case of familial hypertrophic cardiomyopathy emphasizes the importance of parallel screening of multiple disease genes.	Scheffold T	Clinical research in cardiology : official journal of the German Cardiac Society	2011	PMID: 21409595
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547
Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene.	Ehlermann P	BMC medical genetics	2008	PMID: 18957093
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.	Fokstuen S	Human mutation	2008	PMID: 18409188
Shared genetic causes of cardiac hypertrophy in children and adults.	Morita H	The New England journal of medicine	2008	PMID: 18403758
Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE.	Zeller R	Journal of molecular medicine (Berlin, Germany)	2006	PMID: 16715312
Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.	Ingles J	Journal of medical genetics	2005	PMID: 16199542
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15519027
Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.	Erdmann J	Clinical genetics	2003	PMID: 12974739
Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.	Erdmann J	Journal of the American College of Cardiology	2001	PMID: 11499719
click to load more citations click to collapse

Text-mined citations for rs397516037 ...

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 Jul 27, 2026