VCV000042692.26 - ClinVar

NM_000256.3(MYBPC3):c.3233G>A (p.Trp1078Ter)

Germline

Classification

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

Pathogenic
Pathogenic (7)

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.3233G>A (p.Trp1078Ter)

Variation ID: 42692 Accession: VCV000042692.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47333291 (GRCh38) [ NCBI UCSC ] 11: 47354842 (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	Dec 26, 2017	Feb 23, 2026	Sep 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3233G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Trp1078Ter	nonsense
NC_000011.10:g.47333291C>T
NC_000011.9:g.47354842C>T
NG_007667.1:g.24412G>A
LRG_386:g.24412G>A
LRG_386t1:c.3233G>A	LRG_386p1:p.Trp1078Ter

... more HGVS ... less HGVS

Protein change

W1078*

Other names

Canonical SPDI

NC_000011.10:47333290: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: CA013715 dbSNP: rs397516006 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	4829	4851

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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 26, 2025	RCV000533067.13
Hypertrophic cardiomyopathy 4	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 6, 2018	RCV001198904.4
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Mar 1, 2023	RCV001798086.3
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Sep 24, 2025	RCV002444468.4
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 17, 2024	RCV003226900.2

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.
Pathogenic (Jan 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV003923348.2 First in ClinVar: May 13, 2023 Last updated: Sep 16, 2024	Comment: show Reported in association with HCM in a patient referred for genetic testing at GeneDx and in the published literature (PMID: 27532257, 25031304); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25031304, 27532257, 19574547, 27688314) (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 (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005871439.2 First in ClinVar: Mar 04, 2025 Last updated: Oct 05, 2025	Comment: show Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. (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 (May 16, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059215.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: show The p.Trp1078X variant in MYBPC3 has been identified by our laboratory in 4 indi viduals with HCM. It has also been identified in 1/23606 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s397516006). This nonsense variant leads to a premature termination codon at pos ition 1078, which is predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Trp1078X variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon i ts predicted impact to the protein. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 8

Pathogenic (Nov 06, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369899.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: show This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP3,PP5. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Mar 01, 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: SCV002042197.2 First in ClinVar: Dec 29, 2021 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 (Sep 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002611736.4 First in ClinVar: Nov 29, 2022 Last updated: Jan 11, 2026	Publications: PubMed (3) PubMed: 25031304‚ 27532257‚ 27688314 Comment: show The c.3233G>A (p.W1078*) alteration, located in exon 30 (coding exon 30) of the MYBPC3 gene, consists of a G to A substitution at nucleotide position 3233. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 1078. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The Genome Aggregation Database (gnomAD) data for this variant is unreliable due to technical and/or biological issues; therefore, population frequency estimates were not considered. This variant has been detected in individuals with features consistent with hypertrophic cardiomyopathy (Helms, 2014; Helms, 2016; Walsh, 2017). Based on the available evidence, this alteration 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 (Aug 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000623587.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 19574547‚ 25031304 Comment: show This sequence change creates a premature translational stop signal (p.Trp1078*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 25031304). ClinVar contains an entry for this variant (Variation ID: 42692). 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:

Reported in association with HCM in a patient referred for genetic testing at GeneDx and in the published literature (PMID: 27532257, 25031304); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 25031304, 27532257, 19574547, 27688314)

Comment:

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

Comment:

The p.Trp1078X variant in MYBPC3 has been identified by our laboratory in 4 indi viduals with HCM. It has also been identified in 1/23606 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s397516006). This nonsense variant leads to a premature termination codon at pos ition 1078, which is predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Trp1078X variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon i ts predicted impact to the protein.

Comment:

The c.3233G>A (p.W1078*) alteration, located in exon 30 (coding exon 30) of the MYBPC3 gene, consists of a G to A substitution at nucleotide position 3233. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 1078. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The Genome Aggregation Database (gnomAD) data for this variant is unreliable due to technical and/or biological issues; therefore, population frequency estimates were not considered. This variant has been detected in individuals with features consistent with hypertrophic cardiomyopathy (Helms, 2014; Helms, 2016; Walsh, 2017). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Trp1078*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 25031304). ClinVar contains an entry for this variant (Variation ID: 42692). 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
Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy.	Helms AS	Circulation	2016	PMID: 27688314
Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy.	Helms AS	Circulation. Cardiovascular genetics	2014	PMID: 25031304
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs397516006 ...

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 Mar 01, 2026