VCV000042747.20 - ClinVar

NM_000256.3(MYBPC3):c.3G>C (p.Met1Ile)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic (3); Uncertain significance (2)

5 out of 5 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.3G>C (p.Met1Ile)

Variation ID: 42747 Accession: VCV000042747.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47352645 (GRCh38) [ NCBI UCSC ] 11: 47374196 (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 24, 2015	Feb 15, 2026	Nov 24, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Met1Ile	initiator codon variant missense
NC_000011.10:g.47352645C>G
NC_000011.9:g.47374196C>G
NG_007667.1:g.5058G>C
LRG_386:g.5058G>C
LRG_386t1:c.3G>C	LRG_386p1:p.Met1Ile

... more HGVS ... less HGVS

Protein change

M1I

Other names

Canonical SPDI

NC_000011.10:47352644:C:G

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: CA015014 dbSNP: rs397516045 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 specified	Uncertain significance (1)	criteria provided, single submitter	Nov 20, 2019	RCV000035622.6
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 24, 2025	RCV000578781.7
Hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 3, 2025	RCV001245972.8
Cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2025	RCV006547525.1
Hypertrophic cardiomyopathy 4	Likely pathogenic (1)	criteria provided, single submitter	May 30, 2025	RCV005859329.1

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.
Likely pathogenic (Nov 24, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000680825.8 First in ClinVar: Feb 13, 2018 Last updated: Dec 07, 2025	Comment: show Has been reported in association with cardiomyopathy but patient specific details were not provided in these reports (PMID: 25611685, 37652022); Initiation codon variant 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, 28679633, 30297972, 29524613, 25611685, 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

Uncertain significance (Sep 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001419299.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 15, 2026	Publications: PubMed (8) PubMed: 25342278‚ 25611685‚ 27532257‚ 29121657‚ 29524613‚ 30871747‚ 33996946‚ 37652022 Comment: show This sequence change affects the initiator codon of the MYBPC3 mRNA. This change may impact translation initiation or efficiency. The next in-frame methionine is located at codon 103. This variant is present in population databases (rs397516045, gnomAD 0.001%). Disruption of the initiator codon has been observed in individual(s) with MYBPC3-related conditions (PMID: 25611685, 27532257, 29524613, 33996946). ClinVar contains an entry for this variant (Variation ID: 42747). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MYBPC3 protein in which other variant(s) (p.Arg17) have been observed in individuals with MYBPC3-related conditions (PMID: 25342278, 29121657, 30871747, 37652022). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 (Nov 20, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059273.7 First in ClinVar: May 03, 2013 Last updated: Sep 03, 2023	Publications: PubMed (3) PubMed: 25611685‚ 27532257‚ 29524613 Comment: show proposed classification - variant undergoing re-assessment, contact laboratory (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

Likely pathogenic (May 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Institute of Human Genetics, Heidelberg University Accession: SCV006550616.1 First in ClinVar: Oct 05, 2025 Last updated: Oct 05, 2025	Comment: show PVS1, PM2_sup (less) Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: unknown Number of individuals with the variant: 2 Sex: mixed

Likely pathogenic (Sep 13, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV007442004.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 25611685‚ 27532257‚ 30297972‚ 32841044‚ 37652022 Comment: show This variant causes the loss of methionine residue at translation initiation codon 1 in the MYBPC3 protein. This variant is expected to result in the loss of MYBPC3 protein expression. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 30297972, 32841044, 37652022). This variant has been identified in 1/231038 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 gene function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (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:

Has been reported in association with cardiomyopathy but patient specific details were not provided in these reports (PMID: 25611685, 37652022); Initiation codon variant 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, 28679633, 30297972, 29524613, 25611685, 37652022)

Comment:

This sequence change affects the initiator codon of the MYBPC3 mRNA. This change may impact translation initiation or efficiency. The next in-frame methionine is located at codon 103. This variant is present in population databases (rs397516045, gnomAD 0.001%). Disruption of the initiator codon has been observed in individual(s) with MYBPC3-related conditions (PMID: 25611685, 27532257, 29524613, 33996946). ClinVar contains an entry for this variant (Variation ID: 42747). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MYBPC3 protein in which other variant(s) (p.Arg17) have been observed in individuals with MYBPC3-related conditions (PMID: 25342278, 29121657, 30871747, 37652022). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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:

This variant causes the loss of methionine residue at translation initiation codon 1 in the MYBPC3 protein. This variant is expected to result in the loss of MYBPC3 protein expression. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 30297972, 32841044, 37652022). This variant has been identified in 1/231038 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 gene function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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
Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy.	Xiao L	Frontiers in cardiovascular medicine	2021	PMID: 33996946
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
Molecular characterization of Portuguese patients with dilated cardiomyopathy.	Sousa A	Revista portuguesa de cardiologia	2019	PMID: 30871747
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).	Ho CY	Circulation	2018	PMID: 30297972
Whole-exome sequencing identifies rare compound heterozygous mutations in the MYBPC3 gene associated with severe familial hypertrophic cardiomyopathy.	Zhou N	European journal of medical genetics	2018	PMID: 29524613
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.	Viswanathan SK	PloS one	2017	PMID: 29121657
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
Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing.	Gómez J	Circulation journal : official journal of the Japanese Circulation Society	2014	PMID: 25342278

Text-mined citations for rs397516045 ...

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