VCV000042631.14 - ClinVar

NM_000256.3(MYBPC3):c.2518G>A (p.Val840Met)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (6)

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.2518G>A (p.Val840Met)

Variation ID: 42631 Accession: VCV000042631.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337475 (GRCh38) [ NCBI UCSC ] 11: 47359026 (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	Dec 19, 2017	Mar 14, 2026	Dec 2, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2518G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Val840Met	missense
NC_000011.10:g.47337475C>T
NC_000011.9:g.47359026C>T
NG_007667.1:g.20228G>A
LRG_386:g.20228G>A
LRG_386t1:c.2518G>A	LRG_386p1:p.Val840Met

... more HGVS ... less HGVS

Protein change

V840M

Other names

Canonical SPDI

NC_000011.10:47337474: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00006

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA012456 dbSNP: rs376936056 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)	criteria provided, single submitter	May 26, 2010	RCV000035499.7
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 1, 2017	RCV000766354.1
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Mar 23, 2023	RCV001180861.5
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 2, 2025	RCV003996199.4
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Dec 21, 2020	RCV004018749.1
Left ventricular noncompaction 10	Likely pathogenic (1)	criteria provided, single submitter	Nov 5, 2025	RCV006634665.1

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 (Dec 21, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004939708.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: show The c.2518G>A (p.V840M) alteration is located in exon 25 (coding exon 25) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2518, causing the valine (V) at amino acid position 840 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, 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 (Aug 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000616796.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: show A variant of uncertain significance has been identified in the MYBPC3 gene. The V840M variant has not published in a patient with HCM (Walsh et al., 2017); however, additional clinical details and segregation information were not provided. The V840M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the V840M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. (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 (May 26, 2010) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059149.5 First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017	Comment: show The Val840Met has not been reported in the literature, and it also has not been identified in >1000 caucasian probands tested by this laboratory. However, Alig nGVGD and PolyPhen predict the variant is benign, while SIFT predicts that the v ariant is not tolerated. (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

Uncertain Significance (May 04, 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: SCV004839243.1 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 valine with methionine at codon 840 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has also been identified in 5/280216 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: 2 Zygosity: 2 Single Heterozygotes

Uncertain significance (Dec 02, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005693847.2 First in ClinVar: Feb 16, 2025 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 25611685‚ 27532257‚ 37652022 Comment: show This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 840 of the MYBPC3 protein (p.Val840Met). This variant is present in population databases (rs376936056, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42631). 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 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

Likely pathogenic (Nov 05, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Left ventricular noncompaction 10 (Autosomal dominant inheritance)	Medical Genetics Clinic, University of Catania Accession: SCV007496321.1 First in ClinVar: Mar 14, 2026 Last updated: Mar 14, 2026	Comment: show The c.2518G>A variant in the MYBPC3 gene is located in exon 25 of 35 and causes the substitution of a Valine with a Methionine at position 840 (p.Val840Met). In silico prediction tools suggest a possible pathogenic effect on the structure/activity of the protein (MutationTaster: disease causing). The variant frequency in gnomAD (Exome) is 0.0012%. In light of the above, the c.2518G>A variant in the MYBPC3 gene has been classified as a Likely Pathogenic variant. (less) 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 Clinical Features: Noncompaction cardiomyopathy (present) , Palpitations (present) , Premature ventricular contraction (present) Comment on clinical features: The proband was also tested positive for the c.3644A>G (p.Asn121Ser) variant in heterozygosity in the DSP gene and c.2969C>T (p.Ala990Val) in heterozygosity in the VCL gene. Zygosity: 1 Single Heterozygote Age: 40-49 years Ethnicity/Population group: Caucasian Geographic origin: Sicily

Uncertain significance (Mar 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001345902.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (2) PubMed: 25611685‚ 27532257 Comment: show This missense variant replaces valine with methionine at codon 840 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 hypertrophic cardiomyopathy (PMID: 25611685, 27532257). This variant has been identified in 5/280216 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

Comment:

The c.2518G>A (p.V840M) alteration is located in exon 25 (coding exon 25) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2518, causing the valine (V) at amino acid position 840 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

A variant of uncertain significance has been identified in the MYBPC3 gene. The V840M variant has not published in a patient with HCM (Walsh et al., 2017); however, additional clinical details and segregation information were not provided. The V840M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the V840M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.

Comment:

The Val840Met has not been reported in the literature, and it also has not been identified in >1000 caucasian probands tested by this laboratory. However, Alig nGVGD and PolyPhen predict the variant is benign, while SIFT predicts that the v ariant is not tolerated.

Comment:

This missense variant replaces valine with methionine at codon 840 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has also been identified in 5/280216 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:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 840 of the MYBPC3 protein (p.Val840Met). This variant is present in population databases (rs376936056, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 42631). 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 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 c.2518G>A variant in the MYBPC3 gene is located in exon 25 of 35 and causes the substitution of a Valine with a Methionine at position 840 (p.Val840Met). In silico prediction tools suggest a possible pathogenic effect on the structure/activity of the protein (MutationTaster: disease causing). The variant frequency in gnomAD (Exome) is 0.0012%. In light of the above, the c.2518G>A variant in the MYBPC3 gene has been classified as a Likely Pathogenic variant.

Comment:

This missense variant replaces valine with methionine at codon 840 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 hypertrophic cardiomyopathy (PMID: 25611685, 27532257). This variant has been identified in 5/280216 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
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 rs376936056 ...

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 14, 2026