VCV000373084.5 - ClinVar

NM_000256.3(MYBPC3):c.3257G>A (p.Trp1086Ter)

Germline

Classification

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

Pathogenic
Pathogenic (3)

3 out of 4 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.3257G>A (p.Trp1086Ter)

Variation ID: 373084 Accession: VCV000373084.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47333267 (GRCh38) [ NCBI UCSC ] 11: 47354818 (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	Jan 9, 2017	Feb 4, 2024	Jun 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3257G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Trp1086Ter	nonsense
NC_000011.10:g.47333267C>T
NC_000011.9:g.47354818C>T
NG_007667.1:g.24436G>A
LRG_386:g.24436G>A
LRG_386t1:c.3257G>A	LRG_386p1:p.Trp1086Ter

... more HGVS ... less HGVS

Protein change

W1086*

Other names

Canonical SPDI

NC_000011.10:47333266: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.

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA079249 dbSNP: rs779650200 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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 13, 2018	RCV000413654.3
Hypertrophic cardiomyopathy	Pathogenic (1)	no assertion criteria provided	Apr 6, 2020	RCV001254771.1
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jun 16, 2023	RCV003486824.1

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 (Nov 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000491647.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: show The W1086X variant in the MYBPC3 gene has not been reported as a pathogenic variant or as a benign variant to our knowledge. However, a different nucleotide change resulting in the same nonsense variant (c.3258G>A, p.W1086X) has previously been reported in an individual diagnosed with HCM (Murphy et al., 2016). W1086X 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 the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, the W1086X pathogenic variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, W1086X in the MYBPC3 gene is interpreted as a pathogenic variant. (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 (Jul 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000927789.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel	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 16, 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: SCV004239376.1 First in ClinVar: Feb 04, 2024 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 (Apr 06, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV001430873.1 First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020	Publications: PubMed (2) PubMed: 25351510‚ 27532257 Comment: show This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Comment:

The W1086X variant in the MYBPC3 gene has not been reported as a pathogenic variant or as a benign variant to our knowledge. However, a different nucleotide change resulting in the same nonsense variant (c.3258G>A, p.W1086X) has previously been reported in an individual diagnosed with HCM (Murphy et al., 2016). W1086X 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 the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, the W1086X pathogenic variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, W1086X in the MYBPC3 gene is interpreted as a pathogenic variant.

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
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510

Text-mined citations for rs779650200 ...

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 Dec 20, 2025