VCV000164110.10 - ClinVar

NM_000256.3(MYBPC3):c.1540A>G (p.Ile514Val)

Germline

Classification

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

Uncertain significance
Uncertain significance (5)

5 out of 6 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.1540A>G (p.Ile514Val)

Variation ID: 164110 Accession: VCV000164110.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47342662 (GRCh38) [ NCBI UCSC ] 11: 47364213 (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	Feb 23, 2026	Jul 22, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1540A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ile514Val	missense
NC_000011.10:g.47342662T>C
NC_000011.9:g.47364213T>C
NG_007667.1:g.15041A>G
LRG_386:g.15041A>G
LRG_386t1:c.1540A>G	LRG_386p1:p.Ile514Val

... more HGVS ... less HGVS

Protein change

I514V

Other names

Canonical SPDI

NC_000011.10:47342661:T:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA010593 dbSNP: rs727503200 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 specified	Uncertain significance (1)	no assertion criteria provided	Feb 12, 2013	RCV000151127.5
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Sep 30, 2021	RCV002498697.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 3, 2024	RCV004589642.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Mar 4, 2025	RCV005372239.1
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 11, 2025	RCV005089734.2
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 22, 2025	RCV006547647.1

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.
Uncertain significance (Sep 30, 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: SCV002776641.1 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

Uncertain significance (Apr 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005079550.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: show Identified in patients with HCM in published literature (PMID: 37652022, 27532257); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37652022, 27532257) (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

Uncertain significance (Jun 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005729735.2 First in ClinVar: Feb 25, 2025 Last updated: Feb 23, 2026	Publications: PubMed (2) PubMed: 27532257‚ 37652022 Comment: show This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 514 of the MYBPC3 protein (p.Ile514Val). This variant is present in population databases (rs727503200, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 164110). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Uncertain significance (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV006035917.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (2) PubMed: 25611685‚ 27532257 Comment: show The p.I514V variant (also known as c.1540A>G), located in coding exon 17 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 1540. The isoleucine at codon 514 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1 patient with hypertrophic cardiomyopathy (HCM) in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (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

Uncertain significance (Jul 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV007442587.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 25611685‚ 27532257‚ 31229680‚ 37652022 Comment: show This missense variant replaces isoleucine with valine at codon 514 of the MYBPC3 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 37652022) and in an individual affected with either hypertrophic cardiomyopathy or long QT syndrome (PMID: 31229680). This variant has been identified in 2/249270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (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

Uncertain significance (Feb 12, 2013) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198904.3 First in ClinVar: Feb 02, 2015 Last updated: May 29, 2016	Comment: show proposed classification - variant undergoing re-assessment, contact laboratory (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: 1

Comment:

Identified in patients with HCM in published literature (PMID: 37652022, 27532257); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37652022, 27532257)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 514 of the MYBPC3 protein (p.Ile514Val). This variant is present in population databases (rs727503200, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 164110). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.I514V variant (also known as c.1540A>G), located in coding exon 17 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 1540. The isoleucine at codon 514 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1 patient with hypertrophic cardiomyopathy (HCM) in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Comment:

This missense variant replaces isoleucine with valine at codon 514 of the MYBPC3 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 37652022) and in an individual affected with either hypertrophic cardiomyopathy or long QT syndrome (PMID: 31229680). This variant has been identified in 2/249270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.	McGurk KA	American journal of human genetics	2023	PMID: 37652022
Genetic testing and cascade screening in pediatric long QT syndrome and hypertrophic cardiomyopathy.	Knight LM	Heart rhythm	2020	PMID: 31229680
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
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685

Text-mined citations for rs727503200 ...

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