VCV000042755.22 - ClinVar

NM_000256.3(MYBPC3):c.459del (p.Ile154fs)

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (6); Likely pathogenic (1)

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.459del (p.Ile154fs)

Variation ID: 42755 Accession: VCV000042755.22

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11p11.2 11: 47350060 (GRCh38) [ NCBI UCSC ] 11: 47371611 (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	May 29, 2016	Aug 4, 2026	Dec 17, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.459del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ile154fs	frameshift
NM_000256.3:c.459delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47350063del
NC_000011.9:g.47371614del
NG_007667.1:g.7643del
LRG_386:g.7643del
LRG_386t1:c.459del	LRG_386p1:p.Ile154fs

... more HGVS ... less HGVS

Protein change

I154fs

Other names

p.Ile154Leufs*5

Canonical SPDI

NC_000011.10:47350059:GGGG:GGG

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: CA015155 dbSNP: rs397516052 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.
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 10, 2025	RCV000158414.14
Hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 17, 2025	RCV000475909.17
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Pathogenic (1)	criteria provided, single submitter	Sep 23, 2021	RCV002482963.1

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 (Sep 23, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002775668.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 03, 2012) 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: SCV000059281.5 First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016	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: 6

Pathogenic (Apr 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208349.16 First in ClinVar: Feb 24, 2015 Last updated: May 06, 2023	Comment: show Expression studies in neonatal rat ventricular cardiomyocytes showed this variant caused significantly reduced levels of a truncated protein and failed to exhibit sarcomere incorporation when compared to wild-type protein (Glazier et al., 2018); Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 23396983, 21959974, 28640247, 25335496, 29875314) (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 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007137906.1 First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026	Publications: PubMed (3) PubMed: 21959974‚ 27532257‚ 35413566 Comment: show PM2_supporting, PS4_supporting, PVS1 (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 Number of individuals with the variant: 1

Pathogenic (Feb 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV007331094.1 First in ClinVar: Jan 24, 2026 Last updated: Jan 24, 2026	Comment: show The MYBPC3 c.459del; p.Ile154LeufsTer5 variant (rs397516052, ClinVar Variation ID 42755) is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (Bashyam 2012, Manhas 2022, McGurk 2023, Walsh 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bashyam MD et al. A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. Mol Cell Biochem. 2012 Jan;360(1-2):373-82. PMID: 21959974. Manhas et al. Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem Cell Res. 2022 May;61:102774. PMID: 35413566. McGurk et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022 Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. (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 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546475.13 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 19574547‚ 21959974‚ 23396983‚ 25335496‚ 28492532 Comment: show This sequence change creates a premature translational stop signal (p.Ile154Leufs*5) 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: 21959974, 23396983, 25335496). ClinVar contains an entry for this variant (Variation ID: 42755). 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

Likely pathogenic (Dec 22, 2014) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280271.2 First in ClinVar: May 29, 2016 Last updated: Aug 04, 2026	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown

Comment:

Expression studies in neonatal rat ventricular cardiomyocytes showed this variant caused significantly reduced levels of a truncated protein and failed to exhibit sarcomere incorporation when compared to wild-type protein (Glazier et al., 2018); Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 23396983, 21959974, 28640247, 25335496, 29875314)

Comment:

The MYBPC3 c.459del; p.Ile154LeufsTer5 variant (rs397516052, ClinVar Variation ID 42755) is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (Bashyam 2012, Manhas 2022, McGurk 2023, Walsh 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bashyam MD et al. A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. Mol Cell Biochem. 2012 Jan;360(1-2):373-82. PMID: 21959974. Manhas et al. Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem Cell Res. 2022 May;61:102774. PMID: 35413566. McGurk et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022 Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.

Comment:

This sequence change creates a premature translational stop signal (p.Ile154Leufs*5) 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: 21959974, 23396983, 25335496). ClinVar contains an entry for this variant (Variation ID: 42755). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants.	Manhas A	Stem cell research	2022	PMID: 35413566
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
Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.	Wessels MW	European journal of human genetics : EJHG	2015	PMID: 25335496
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India.	Bashyam MD	Molecular and cellular biochemistry	2012	PMID: 21959974
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs397516052 ...

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 Aug 04, 2026