VCV000217835.13 - ClinVar

NM_000256.3(MYBPC3):c.1359del (p.Val454fs)

Germline

Classification

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

Pathogenic
Pathogenic (4)

4 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.1359del (p.Val454fs)

Variation ID: 217835 Accession: VCV000217835.13

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11p11.2 11: 47342928 (GRCh38) [ NCBI UCSC ] 11: 47364479 (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	Nov 14, 2015	Apr 25, 2026	Dec 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1359del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Val454fs	frameshift
NM_000256.3:c.1359delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47342928del
NC_000011.9:g.47364479del
NG_007667.1:g.14775del
LRG_386:g.14775del
LRG_386t1:c.1359del	LRG_386p1:p.Val454fs

... more HGVS ... less HGVS

Protein change

V454fs

Other names

Canonical SPDI

NC_000011.10:47342927: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA279624 dbSNP: rs863225271 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	4728	4750

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 1	Pathogenic (1)	criteria provided, single submitter	May 1, 2015	RCV000201912.2
Hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 13, 2023	RCV001209345.12
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 29, 2025	RCV006659309.1

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 (May 01, 2015) C Contributing to aggregate classification	criteria provided, single submitter (Agnes Ginges Centre for Molecular Cardiology criteria (2015))	Hypertrophic cardiomyopathy 1 (Autosomal dominant inheritance)	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV000256658.2 First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015	Comment: show This MYBPC3 Val454Cysfs*12 variant is predicted to cause a frameshift starting at codon 454, and lead to a premature stop codon 11 amino acids downstream. This variant has been identified in our laboratory in a patient with a diagnosis of HCM. Co-segregation data from our laboratory showed that 3 affected individuals in the family all carried the variant. This frameshift variant is not reported in the literature and is not present in both the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Based on its absence in the general population. familial segregation of the variant with disease in our family, and that loss-of-function mutations in the MYBPC3 gene are an established mechanism of disease in HCM, this variant is categorised by our group as "pathogenic". (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

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: SCV004847805.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (3) PubMed: 25351510‚ 27532257‚ 28615295 Comment: show The p.Val454CysfsX12 variant in MYBPC3 has been reported in 3 individuals with hypertrophic cardiomyopathy and segregated with disease in 2 family members (Lopes 2015, Walsh 2017, Ross 2017). It was absent from large population studies but has been reported in ClinVar (Variation ID 217835). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 454 and leads to a premature termination codon 12 amino acids downstream. This alteration is then 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 (Jun 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001380775.7 First in ClinVar: Jul 16, 2020 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 19574547‚ 25351510‚ 27532257 Comment: show This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 27532257). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217835). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val454Cysfs*12) 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). (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 (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV007570942.1 First in ClinVar: Apr 25, 2026 Last updated: Apr 25, 2026	Publications: PubMed (5) PubMed: 27532257‚ 28615295‚ 29021349‚ 30775854‚ 36578016 Comment: show The c.1359delT pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1359, causing a translational frameshift with a predicted alternate stop codon (p.V454Cfs*12). This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Singh SR et al. Circ Heart Fail, 2017 Oct;10:; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Stafford F et al. Genome Med, 2022 Dec;14:145). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:

This MYBPC3 Val454Cysfs*12 variant is predicted to cause a frameshift starting at codon 454, and lead to a premature stop codon 11 amino acids downstream. This variant has been identified in our laboratory in a patient with a diagnosis of HCM. Co-segregation data from our laboratory showed that 3 affected individuals in the family all carried the variant. This frameshift variant is not reported in the literature and is not present in both the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Based on its absence in the general population. familial segregation of the variant with disease in our family, and that loss-of-function mutations in the MYBPC3 gene are an established mechanism of disease in HCM, this variant is categorised by our group as "pathogenic".

Comment:

The p.Val454CysfsX12 variant in MYBPC3 has been reported in 3 individuals with hypertrophic cardiomyopathy and segregated with disease in 2 family members (Lopes 2015, Walsh 2017, Ross 2017). It was absent from large population studies but has been reported in ClinVar (Variation ID 217835). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 454 and leads to a premature termination codon 12 amino acids downstream. This alteration is then 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 premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 27532257). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217835). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val454Cysfs*12) 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).

Comment:

The c.1359delT pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1359, causing a translational frameshift with a predicted alternate stop codon (p.V454Cfs*12). This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Singh SR et al. Circ Heart Fail, 2017 Oct;10:; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Stafford F et al. Genome Med, 2022 Dec;14:145). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic.	Stafford F	Genome medicine	2022	PMID: 36578016
Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy.	Jääskeläinen P	ESC heart failure	2019	PMID: 30775854
Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3-Targeted Knockin Mice.	Singh SR	Circulation. Heart failure	2017	PMID: 29021349
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy.	Ross SB	Circulation. Cardiovascular genetics	2017	PMID: 28615295
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
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs863225271 ...

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 03, 2026