VCV001406676.15 - ClinVar

NM_000256.3(MYBPC3):c.1A>T (p.Met1Leu)

Germline

Classification

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

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

6 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.1A>T (p.Met1Leu)

Variation ID: 1406676 Accession: VCV001406676.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47352647 (GRCh38) [ NCBI UCSC ] 11: 47374198 (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	Mar 28, 2022	Feb 15, 2026	Sep 27, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Met1Leu	initiator codon variant missense
NC_000011.10:g.47352647T>A
NC_000011.9:g.47374198T>A
NG_007667.1:g.5056A>T
LRG_386:g.5056A>T
LRG_386t1:c.1A>T	LRG_386p1:p.Met1Leu

... more HGVS ... less HGVS

Protein change

M1L

Other names

Canonical SPDI

NC_000011.10:47352646:T:A

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA380342848 dbSNP: rs1461764618 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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 27, 2025	RCV001915932.10
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	May 5, 2023	RCV003303363.2
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Apr 21, 2022	RCV003150467.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 20, 2024	RCV005250214.1
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Likely pathogenic (1)	criteria provided, single submitter	Jan 6, 2024	RCV005050452.1

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 (Apr 21, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838292.2 First in ClinVar: Mar 11, 2023 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 25741868 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 30, 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: SCV004842949.1 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)	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: 1 Zygosity: 1 Single Heterozygote

Likely pathogenic (May 05, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV003997507.3 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27532257 Comment: show The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the MYBPC3 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been detected in an individual from a cohort referred for hypertrophic cardiomyopathy genetic testing. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be 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

Likely pathogenic (Jan 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV005684643.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 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

Likely pathogenic (Sep 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005900861.1 First in ClinVar: Mar 29, 2025 Last updated: Mar 29, 2025	Comment: show Reported in individuals with cardiomyopathy from large cohort studies, although further patient-specific details were limited (PMID: 37652022, 27532257); 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, 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 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002177925.6 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 25611685‚ 26090888‚ 27532257‚ 29524613‚ 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 not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 29524613, 33996946, 37652022). ClinVar contains an entry for this variant (Variation ID: 1406676). 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.Ile49Ser) have been observed in individuals with MYBPC3-related conditions (PMID: 26090888). 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

Comment:

The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the MYBPC3 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant has been detected in an individual from a cohort referred for hypertrophic cardiomyopathy genetic testing. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

Reported in individuals with cardiomyopathy from large cohort studies, although further patient-specific details were limited (PMID: 37652022, 27532257); 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, 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 not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 29524613, 33996946, 37652022). ClinVar contains an entry for this variant (Variation ID: 1406676). 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.Ile49Ser) have been observed in individuals with MYBPC3-related conditions (PMID: 26090888). 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.

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
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
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
Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing.	Liu X	Scientific reports	2015	PMID: 26090888
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
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 rs1461764618 ...

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