VCV000181022.27 - ClinVar

NM_000256.3(MYBPC3):c.3771C>A (p.Asn1257Lys)

Germline

Classification

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

Conflicting classifications of pathogenicity
Pathogenic (1); Likely pathogenic (3); Uncertain significance (3)

7 out of 8 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.3771C>A (p.Asn1257Lys)

Variation ID: 181022 Accession: VCV000181022.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332115 (GRCh38) [ NCBI UCSC ] 11: 47353666 (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	Jun 1, 2016	Aug 4, 2026	Dec 14, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3771C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Asn1257Lys	missense
NC_000011.10:g.47332115G>T
NC_000011.9:g.47353666G>T
NG_007667.1:g.25588C>A
LRG_386:g.25588C>A
LRG_386t1:c.3771C>A	LRG_386p1:p.Asn1257Lys

... more HGVS ... less HGVS

Protein change

N1257K

Other names

p.N1257K:AAC>AAA

Canonical SPDI

NC_000011.10:47332114:G: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.

Links

ClinGen: CA014838 dbSNP: rs730880603 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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 26, 2016	RCV000215436.8
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2025	RCV000234005.12
not provided	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Dec 5, 2025	RCV000766381.7
Asymmetric septal hypertrophy	Likely pathogenic (1)	no assertion criteria provided	Jan 1, 2018	RCV001251033.1
Cardiovascular phenotype	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Jul 28, 2025	RCV002345534.4
Hypertrophic cardiomyopathy 4	Likely pathogenic (1)	criteria provided, single submitter	Jul 18, 2025	RCV006704583.1

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 (Jan 26, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified (Autosomal dominant inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000271995.2 First in ClinVar: May 29, 2016 Last updated: Dec 19, 2017	Publications: PubMed (4) PubMed: 12818575‚ 23396983‚ 24510615‚ 25351510 Comment: show Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asn1257Ly s variant in MYBPC3 has been reported in at least 7 individuals with HCM (Lopes 2013, Kapplinger 2014, Lopes 2015). This variant was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that the p.Asn1257Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Asn1257Lys va riant is uncertain. (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: 2

Likely pathogenic (Apr 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiovascular phenotype	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987611.2 First in ClinVar: Sep 08, 2019 Last updated: Aug 23, 2025	Comment: show PS4, PM2, PS3_supp (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 (Jul 28, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002623409.3 First in ClinVar: Nov 29, 2022 Last updated: Oct 05, 2025	Publications: PubMed (5) PubMed: 24510615‚ 24793961‚ 27532257‚ 29030401‚ 32841044 Comment: show The p.N1257K variant (also known as c.3771C>A), located in coding exon 33 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3771. The asparagine at codon 1257 is replaced by lysine, an amino acid with similar properties. This variant has been observed in multiple individuals reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10:[Epub ahead of print]). This amino acid position is highly 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

Likely pathogenic (Dec 05, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208196.15 First in ClinVar: Feb 24, 2015 Last updated: Dec 27, 2025	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect in HEK293A cells (PMID: 32841044); 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: 23396983, 24510615, 24793961, 27532257, 12818575, 25351510, 29030401, 33782553, 32841044, 37652022, 38456273) (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

Pathogenic (Dec 14, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284245.11 First in ClinVar: Jul 01, 2016 Last updated: Mar 07, 2026	Publications: PubMed (6) PubMed: 23396983‚ 24510615‚ 24793961‚ 27532257‚ 29030401‚ 32841044 Comment: show This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1257 of the MYBPC3 protein (p.Asn1257Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with known and suspected hypertrophic cardiomyopathy (HCM) (PMID: 23396983, 24510615, 24793961, 27532257, 29030401; internal data). ClinVar contains an entry for this variant (Variation ID: 181022). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 32841044). For these reasons, this variant has been classified as 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 (Oct 01, 2013) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280269.2 First in ClinVar: Jun 01, 2016 Last updated: Aug 04, 2026	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: unknown

Likely pathogenic (Jul 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV007608165.1 First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026	Publications: PubMed (1) PubMed: 23396983 Comment: show The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.57 (damaging >=0.6, benign <0.4), 3Cnet: 0.24 (damaging >0.75, benign <0.1)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181022 /PMID: 23396983 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

Likely pathogenic (Jan 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Asymmetric septal hypertrophy	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001426426.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020	Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asn1257Ly s variant in MYBPC3 has been reported in at least 7 individuals with HCM (Lopes 2013, Kapplinger 2014, Lopes 2015). This variant was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that the p.Asn1257Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Asn1257Lys va riant is uncertain.

Comment:

The p.N1257K variant (also known as c.3771C>A), located in coding exon 33 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3771. The asparagine at codon 1257 is replaced by lysine, an amino acid with similar properties. This variant has been observed in multiple individuals reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10:[Epub ahead of print]). This amino acid position is highly 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:

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect in HEK293A cells (PMID: 32841044); 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: 23396983, 24510615, 24793961, 27532257, 12818575, 25351510, 29030401, 33782553, 32841044, 37652022, 38456273)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1257 of the MYBPC3 protein (p.Asn1257Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with known and suspected hypertrophic cardiomyopathy (HCM) (PMID: 23396983, 24510615, 24793961, 27532257, 29030401; internal data). ClinVar contains an entry for this variant (Variation ID: 181022). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 32841044). For these reasons, this variant has been classified as Pathogenic.

Comment:

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.57 (damaging >=0.6, benign <0.4), 3Cnet: 0.24 (damaging >0.75, benign <0.1)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181022 /PMID: 23396983 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients.	Cirino AL	Circulation. Cardiovascular genetics	2017	PMID: 29030401
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
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden.	Mörner S	Journal of molecular and cellular cardiology	2003	PMID: 12818575

Text-mined citations for rs730880603 ...

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 Aug 04, 2026