VCV000180934.4 - ClinVar

NM_000256.3(MYBPC3):c.1405C>T (p.Gln469Ter)

Germline

Classification

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

Pathogenic
Pathogenic (2)

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.1405C>T (p.Gln469Ter)

Variation ID: 180934 Accession: VCV000180934.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47342882 (GRCh38) [ NCBI UCSC ] 11: 47364433 (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 24, 2015	May 1, 2024	Jun 29, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1405C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gln469Ter	nonsense
NC_000011.10:g.47342882G>A
NC_000011.9:g.47364433G>A
NG_007667.1:g.14821C>T
LRG_386:g.14821C>T
LRG_386t1:c.1405C>T	LRG_386p1:p.Gln469Ter

... more HGVS ... less HGVS

Protein change

Q469*

Other names

p.Q469*:CAG>TAG

Canonical SPDI

NC_000011.10:47342881: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: CA010259 dbSNP: rs730880539 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	Nov 11, 2013	RCV000158082.1
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jun 29, 2022	RCV002390377.2

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 (Nov 11, 2013) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000208017.10 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Comment: show p.Gln469Stop (CAG>TAG): c.1405 C>T in exon 16 of the MYBPC3 gene (NM_000256.3) The Gln469Stop mutation in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gln469Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln469Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s). (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 29, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002699180.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 27532257‚ 32841044‚ 33586461 Comment: show The p.Q469* pathogenic mutation (also known as c.1405C>T), located in coding exon 16 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1405. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This alteration has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Walsh R et al. Genet Med, 2017 02;19:192-203; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Wu G et al. J Am Heart Assoc, 2021 02;10:e018236). In addition to the clinical data presented in the literature, 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

Comment:

p.Gln469Stop (CAG>TAG): c.1405 C>T in exon 16 of the MYBPC3 gene (NM_000256.3) The Gln469Stop mutation in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gln469Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln469Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).

Comment:

The p.Q469* pathogenic mutation (also known as c.1405C>T), located in coding exon 16 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1405. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This alteration has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Walsh R et al. Genet Med, 2017 02;19:192-203; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Wu G et al. J Am Heart Assoc, 2021 02;10:e018236). In addition to the clinical data presented in the literature, 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy.	Wu G	Journal of the American Heart Association	2021	PMID: 33586461
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.	Helms AS	Circulation. Genomic and precision medicine	2020	PMID: 32841044
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

Text-mined citations for rs730880539 ...

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 01, 2024