VCV000488797.14 - ClinVar

NM_000256.3(MYBPC3):c.1303C>T (p.Gln435Ter)

Germline

Classification

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

Pathogenic
Pathogenic (5)

5 out of 5 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.1303C>T (p.Gln435Ter)

Variation ID: 488797 Accession: VCV000488797.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47343069 (GRCh38) [ NCBI UCSC ] 11: 47364620 (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	Feb 13, 2018	Jun 20, 2026	Jan 16, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1303C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gln435Ter	nonsense
NC_000011.10:g.47343069G>A
NC_000011.9:g.47364620G>A
NG_007667.1:g.14634C>T
LRG_386:g.14634C>T
LRG_386t1:c.1303C>T	LRG_386p1:p.Gln435Ter

... more HGVS ... less HGVS

Protein change

Q435*

Other names

Canonical SPDI

NC_000011.10:47343068: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: CA380327136 dbSNP: rs1432810664 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 (1)	criteria provided, single submitter	Jun 5, 2023	RCV000579171.4
Hypertrophic cardiomyopathy 4	Pathogenic (1)	criteria provided, single submitter	Jan 16, 2026	RCV001809678.5
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Feb 18, 2021	RCV001805196.2
Hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 16, 2025	RCV003586195.5

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 (Feb 18, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV002053547.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: show This variant changes 1 nucleotide in exon 15 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 23396983, 27532257). This variant has not been identified 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 (Jun 05, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000680669.4 First in ClinVar: Feb 13, 2018 Last updated: Jun 17, 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 25985138, 23396983, 25228707, 25351510, 33087929, 35177841) (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 (Jan 16, 2026) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV002058238.3 First in ClinVar: Jan 15, 2022 Last updated: Jun 20, 2026	Publications: PubMed (1) PubMed: 23396983 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000488797 /PMID: 23396983 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (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 Platform type: exome sequencing

Pathogenic (Oct 14, 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: SCV004847812.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 23396983‚ 27532257 Comment: show The p.Gln435X variant in MYBPC3 has been reported in 2 individuals with HCM (Lopes 2013, Walsh 2017). It was absent from large population studies but has been reported in ClinVar (Variation ID 488797). This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. (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 16, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004294809.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 19574547‚ 23396983 Comment: show This sequence change creates a premature translational stop signal (p.Gln435*) 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: 23396983). ClinVar contains an entry for this variant (Variation ID: 488797). 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:

This variant changes 1 nucleotide in exon 15 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 23396983, 27532257). This variant has not been identified 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:

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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 25985138, 23396983, 25228707, 25351510, 33087929, 35177841)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000488797 /PMID: 23396983 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The p.Gln435X variant in MYBPC3 has been reported in 2 individuals with HCM (Lopes 2013, Walsh 2017). It was absent from large population studies but has been reported in ClinVar (Variation ID 488797). This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting.

Comment:

This sequence change creates a premature translational stop signal (p.Gln435*) 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: 23396983). ClinVar contains an entry for this variant (Variation ID: 488797). 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
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs1432810664 ...

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 Jun 27, 2026