VCV000181002.35 - ClinVar

NM_000256.3(MYBPC3):c.3154A>G (p.Met1052Val)

Germline

Classification

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

Conflicting classifications of pathogenicity
Uncertain significance (6); Likely benign (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.3154A>G (p.Met1052Val)

Variation ID: 181002 Accession: VCV000181002.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47355144 (GRCh37) [ NCBI UCSC ] 11: 47333593 (GRCh38) [ 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 15, 2026	Jan 7, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3154A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Met1052Val	missense
NC_000011.10:g.47333593T>C
NC_000011.9:g.47355144T>C
NG_007667.1:g.24110A>G
LRG_386:g.24110A>G
LRG_386t1:c.3154A>G	LRG_386p1:p.Met1052Val

... more HGVS ... less HGVS

Protein change

M1052V

Other names

p.M1052V:ATG>GTG

Canonical SPDI

NC_000011.10:47333592: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.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA013559 dbSNP: rs730880589 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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 17, 2023	RCV000158218.13
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 7, 2026	RCV001209565.11
Cardiomyopathy	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Feb 18, 2025	RCV001171136.8
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Dec 19, 2022	RCV002321661.3

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 (Mar 02, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333817.2 First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021	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 (Dec 19, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002608539.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27532257 Comment: show The p.M1052V variant (also known as c.3154A>G), located in coding exon 29 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 3154. The methionine at codon 1052 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 (Jan 07, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001381005.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 27532257 Comment: show This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the MYBPC3 protein (p.Met1052Val). This variant is present in population databases (rs730880589, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181002). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 (Oct 16, 2019) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208153.14 First in ClinVar: Feb 24, 2015 Last updated: Jul 24, 2021	Comment: show Reported in a patient referred for DCM genetic testing; however, additional clinical information was not provided (Walsh et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 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 (Dec 18, 2023) 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: SCV004836649.1 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 (1) PubMed: 27532257 Comment: show This missense variant replaces methionine with valine at codon 1052 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 11/272206 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: 6 Zygosity: 6 Single Heterozygotes

Likely benign (Feb 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001352613.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	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 (Oct 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV006317256.1 First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 2025	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:

The p.M1052V variant (also known as c.3154A>G), located in coding exon 29 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 3154. The methionine at codon 1052 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the MYBPC3 protein (p.Met1052Val). This variant is present in population databases (rs730880589, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181002). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:

Reported in a patient referred for DCM genetic testing; however, additional clinical information was not provided (Walsh et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)

Comment:

This missense variant replaces methionine with valine at codon 1052 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 11/272206 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
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 rs730880589 ...

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 Feb 15, 2026