VCV000219403.21 - ClinVar

NM_000256.3(MYBPC3):c.1153G>A (p.Val385Met)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (7)

8 out of 9 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.1153G>A (p.Val385Met)

Variation ID: 219403 Accession: VCV000219403.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47343562 (GRCh38) [ NCBI UCSC ] 11: 47365113 (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 2, 2016	Feb 23, 2026	Jan 27, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1153G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Val385Met	missense
NC_000011.10:g.47343562C>T
NC_000011.9:g.47365113C>T
NG_007667.1:g.14141G>A
LRG_386:g.14141G>A
LRG_386t1:c.1153G>A	LRG_386p1:p.Val385Met

... more HGVS ... less HGVS

Protein change

V385M

Other names

Canonical SPDI

NC_000011.10:47343561:C:T

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA042951 dbSNP: rs772073491 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	4724	4746

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	Conflicting classifications of pathogenicity (4)	criteria provided, conflicting classifications	Jan 27, 2026	RCV000206400.13
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2024	RCV001184019.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jan 15, 2025	RCV002345726.3
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Jul 26, 2021	RCV002503799.1
Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Mar 7, 2024	RCV003991469.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2025	RCV005623313.1

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 (Oct 31, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Center for Human Genetics, University of Leuven Accession: SCV000886819.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019	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 (Jul 26, 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: SCV002796999.1 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 (Mar 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Left ventricular noncompaction 10	KardioGenetik, Herz- und Diabeteszentrum NRW Accession: SCV004809099.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Jan 15, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002623178.3 First in ClinVar: Nov 29, 2022 Last updated: Apr 28, 2025	Publications: PubMed (8) PubMed: 21750094‚ 22958901‚ 27532257‚ 29687901‚ 31513939‚ 32356610‚ 32841044‚ 36788754 Comment: show The p.V385M variant (also known as c.1153G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1153. The valine at codon 385 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in various cardiomyopathy cohorts, including dilated cardiomyopathy cohorts and hypertrophic cardiomyopathy cohorts; however, clinical details were limited in some cases and additional alterations were identified in other cardiac-related genes (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Walsh R et al. Genet Med, 2017 02;19:192-203; Wang L et al. Compr Physiol, 2018 03;8:631-709; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Piriou N et al. ESC Heart Fail, 2020 May:[ePub ahead of print]; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has been reported in the Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration 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 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001349890.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (7) PubMed: 21750094‚ 27532257‚ 31513939‚ 32356610‚ 32841044‚ 33782553‚ 34097875 Comment: show This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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 (Jan 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV006304438.1 First in ClinVar: Aug 09, 2025 Last updated: Aug 09, 2025	Comment: show Identified in patients with cardiomyopathy in published literature; at least one individual harbored an additional cardiogenetic variant (PMID: 21750094, 22958901, 27532257, 32356610, 31513939, 36788754, 37652022, 33782553); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 34097875, 27532257, 31513939, 32356610, 33782553, 36788754, 32841044, 21750094, 37652022) (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

Likely pathogenic (Jan 27, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259253.9 First in ClinVar: Feb 02, 2016 Last updated: Feb 23, 2026	Publications: PubMed (9) PubMed: 21750094‚ 27532257‚ 28492532‚ 31513939‚ 32841044‚ 33782553‚ 36788754‚ 37652022‚ 38456273 Comment: show This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 385 of the MYBPC3 protein (p.Val385Met). This variant is present in population databases (rs772073491, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertropic cardiomyopathy (PMID: 21750094, 27532257, 31513939, 32841044, 33782553, 36788754, 37652022, 38456273; internal data). ClinVar contains an entry for this variant (Variation ID: 219403). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Uncertain Significance (Jan 11, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004834664.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (7) PubMed: 21750094‚ 27532257‚ 31513939‚ 32356610‚ 32841044‚ 33782553‚ 34097875 Comment: show This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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 Number of individuals with the variant: 10 Zygosity: 10 Single Heterozygotes

Uncertain significance (Aug 01, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: CSER - NEXT Medicine variant annotation Accession: SCV000503534.1 First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016	Comment: show Found in patient having exome sequencing for an unrelated indication. No known history of cardiomyopathy. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Comment:

The p.V385M variant (also known as c.1153G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1153. The valine at codon 385 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in various cardiomyopathy cohorts, including dilated cardiomyopathy cohorts and hypertrophic cardiomyopathy cohorts; however, clinical details were limited in some cases and additional alterations were identified in other cardiac-related genes (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Walsh R et al. Genet Med, 2017 02;19:192-203; Wang L et al. Compr Physiol, 2018 03;8:631-709; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Piriou N et al. ESC Heart Fail, 2020 May:[ePub ahead of print]; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has been reported in the Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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.

Comment:

Identified in patients with cardiomyopathy in published literature; at least one individual harbored an additional cardiogenetic variant (PMID: 21750094, 22958901, 27532257, 32356610, 31513939, 36788754, 37652022, 33782553); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 34097875, 27532257, 31513939, 32356610, 33782553, 36788754, 32841044, 21750094, 37652022)

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 385 of the MYBPC3 protein (p.Val385Met). This variant is present in population databases (rs772073491, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertropic cardiomyopathy (PMID: 21750094, 27532257, 31513939, 32841044, 33782553, 36788754, 37652022, 38456273; internal data). ClinVar contains an entry for this variant (Variation ID: 219403). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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
Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.	Earle NJ	Circulation. Heart failure	2024	PMID: 38456273
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
Whole-exome sequencing: Clinical characterization of pediatric and adult Italian patients affected by different forms of hereditary cardiovascular diseases.	Lenarduzzi S	Molecular genetics & genomic medicine	2023	PMID: 36788754
Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.	Suay-Corredera C	The Journal of biological chemistry	2021	PMID: 34097875
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.	Thompson AD	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33782553
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
Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.	Piriou N	ESC heart failure	2020	PMID: 32356610
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Thick Filament Protein Network, Functions, and Disease Association.	Wang L	Comprehensive Physiology	2018	PMID: 29687901
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
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.	Bick AG	American journal of human genetics	2012	PMID: 22958901
Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure.	Waldmüller S	European journal of heart failure	2011	PMID: 21750094
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Text-mined citations for rs772073491 ...

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