VCV000418352.9 - ClinVar

NM_000256.3(MYBPC3):c.747C>A (p.Cys249Ter)

Germline

Classification

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

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

2 out of 2 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.747C>A (p.Cys249Ter)

Variation ID: 418352 Accession: VCV000418352.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47348449 (GRCh38) [ NCBI UCSC ] 11: 47370000 (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	Apr 27, 2017	Feb 15, 2026	Sep 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.747C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Cys249Ter	nonsense
NC_000011.10:g.47348449G>T
NC_000011.9:g.47370000G>T
NG_007667.1:g.9254C>A
LRG_386:g.9254C>A
LRG_386t1:c.747C>A	LRG_386p1:p.Cys249Ter

... more HGVS ... less HGVS

Protein change

C249*

Other names

Canonical SPDI

NC_000011.10:47348448:G: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) 0.00001

Links

ClinGen: CA16619343 dbSNP: rs771929829 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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Feb 13, 2017	RCV000478526.1
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Sep 23, 2022	RCV000694565.9

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 (Feb 13, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000565272.4 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Comment: show The C249X likely pathogenic variant in the MYBPC3 gene has not been reported as a pathogenic or benign to our knowledge. C249X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, the C249X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). (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 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000823016.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 19574547‚ 27532257‚ 28492532 Comment: show This sequence change creates a premature translational stop signal (p.Cys249*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 418352). 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

Comment:

The C249X likely pathogenic variant in the MYBPC3 gene has not been reported as a pathogenic or benign to our knowledge. C249X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other downstream nonsense variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, the C249X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

Comment:

This sequence change creates a premature translational stop signal (p.Cys249*) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 418352). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 rs771929829 ...

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 Feb 15, 2026