VCV000217478.22 - ClinVar

NM_000256.3(MYBPC3):c.2371C>T (p.Gln791Ter)

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (6); Likely pathogenic (1)

7 out of 7 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.2371C>T (p.Gln791Ter)

Variation ID: 217478 Accession: VCV000217478.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337732 (GRCh38) [ NCBI UCSC ] 11: 47359283 (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	Nov 5, 2015	May 30, 2026	Feb 26, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2371C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gln791Ter	nonsense
NC_000011.10:g.47337732G>A
NC_000011.9:g.47359283G>A
NG_007667.1:g.19971C>T
LRG_386:g.19971C>T
LRG_386t1:c.2371C>T	LRG_386p1:p.Gln791Ter

... more HGVS ... less HGVS

Protein change

Q791*

Other names

Canonical SPDI

NC_000011.10:47337731: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.

Links

ClinGen: CA279318 dbSNP: rs863225106 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.
Hypertrophic cardiomyopathy 4	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 26, 2026	RCV000201498.4
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Nov 22, 2022	RCV000618778.4
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2024	RCV001089632.10
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jun 12, 2020	RCV001170420.3
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 3, 2020	RCV001537119.2

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.
Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (LGCM Criteria August 2015)	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance)	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe) Accession: SCV000256167.1 First in ClinVar: Nov 05, 2015 Last updated: Nov 05, 2015	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 (Dec 03, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001753952.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: show Has been reported in association with HCM in published literature (Walsh et al., 2017; Lu et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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 as pathogenic or likely pathogenic (ClinVar Variant ID# 217478; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 30165862) (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 (Jun 12, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001332998.2 First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021	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 (Nov 22, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000740176.6 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: show The p.Q791* pathogenic mutation (also known as c.2371C>T), located in coding exon 24 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2371. This changes the amino acid from a glutamine to a stop codon within coding exon 24. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 07, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance)	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV001245110.2 First in ClinVar: May 04, 2020 Last updated: Feb 08, 2025	Publications: PubMed (1) PubMed: 27532257 Comment: show MYBPC3 Gln791Ter has been previously reported in 1 HCM proband (Walsh R, et al., 2017) and has been identified in a HCM proband from both Royal Brisbane Hospital and the University de Sao Paulo (Pers. Comm.). We identified this variant in an individual diagnosed with HCM. This patient's deceased father died suddenly and was suspected to have HCM on postmortem, segregation analysis was however not possible. The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been identified in at least 4 probands (PS4_supporting), therefore we classify MYBPC3 Gln791Ter as 'pathogenic'. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Pathogenic (Jan 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001590846.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 19574547‚ 27532257‚ 30165862 Comment: show This sequence change creates a premature translational stop signal (p.Gln791*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30165862). ClinVar contains an entry for this variant (Variation ID: 217478). 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 (Feb 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Institute of Immunology and Genetics Kaiserslautern Accession: SCV007596617.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Comment: show ACMG Criteria: PVS1, PS4_M, PM2; 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)

Comment:

Has been reported in association with HCM in published literature (Walsh et al., 2017; Lu et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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 as pathogenic or likely pathogenic (ClinVar Variant ID# 217478; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 30165862)

Comment:

The p.Q791* pathogenic mutation (also known as c.2371C>T), located in coding exon 24 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2371. This changes the amino acid from a glutamine to a stop codon within coding exon 24. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:

MYBPC3 Gln791Ter has been previously reported in 1 HCM proband (Walsh R, et al., 2017) and has been identified in a HCM proband from both Royal Brisbane Hospital and the University de Sao Paulo (Pers. Comm.). We identified this variant in an individual diagnosed with HCM. This patient's deceased father died suddenly and was suspected to have HCM on postmortem, segregation analysis was however not possible. The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been identified in at least 4 probands (PS4_supporting), therefore we classify MYBPC3 Gln791Ter as 'pathogenic'.

Comment:

This sequence change creates a premature translational stop signal (p.Gln791*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30165862). ClinVar contains an entry for this variant (Variation ID: 217478). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies.	Lu C	Journal of translational medicine	2018	PMID: 30165862
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
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs863225106 ...

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 May 30, 2026