VCV000407308.14 - ClinVar

NM_000256.3(MYBPC3):c.2265C>A (p.Asn755Lys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (3)

4 out of 4 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.2265C>A (p.Asn755Lys)

Variation ID: 407308 Accession: VCV000407308.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47338563 (GRCh38) [ NCBI UCSC ] 11: 47360114 (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	May 26, 2018	Feb 15, 2026	Oct 2, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2265C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Asn755Lys	missense
NC_000011.10:g.47338563G>T
NC_000011.9:g.47360114G>T
NG_007667.1:g.19140C>A
LRG_386:g.19140C>A
LRG_386t1:c.2265C>A	LRG_386p1:p.Asn755Lys

... more HGVS ... less HGVS

Protein change

N755K

Other names

Canonical SPDI

NC_000011.10:47338562: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA16613387 dbSNP: rs1060501474 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	Pathogenic (1)	criteria provided, single submitter	May 27, 2024	RCV000473072.11
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Oct 2, 2025	RCV002446801.3
Hypertrophic cardiomyopathy 4	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV005001987.4

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 (Oct 02, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002733417.3 First in ClinVar: Nov 29, 2022 Last updated: Jan 11, 2026	Publications: PubMed (12) PubMed: 12386140‚ 12386147‚ 15166115‚ 15370892‚ 18803133‚ 21310275‚ 22173300‚ 27532257‚ 34714385‚ 38042491‚ 9541100‚ 9541104 Comment: show The p.N755K variant (also known as c.2265C>A), located in coding exon 23 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 2265. The asparagine at codon 755 is replaced by lysine, an amino acid with similar properties. This variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy, segregated with disease in at least one family, and was determined to be de novo in at least one individual (Yu B et al. J Med Genet, 1998 Mar;35:183-8; Yu B et al. J Med Genet, 1998 Mar;35:205-10; Rudziski T et al. Kardiol Pol, 2008 Aug;66:821-5; discussion 826-7; Walsh R et al. Genet Med, 2017 02;19:192-203; Gal DB et al. Pediatr Cardiol. 2022 Mar;43(3):616-623; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Pathogenic (May 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546409.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 12386147‚ 12787675‚ 18803133‚ 9541100‚ 9541104 Comment: show This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 755 of the MYBPC3 protein (p.Asn755Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9541100, 9541104, 18803133; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407308). 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: 12386147, 12787675). 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

Likely pathogenic (Feb 15, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020)	Hypertrophic cardiomyopathy 4	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust Accession: SCV005627620.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (12) PubMed: 12386140‚ 12386147‚ 12787675‚ 15166115‚ 18803133‚ 21310275‚ 22173300‚ 27532257‚ 37652022‚ 38042491‚ 9541100‚ 9541104 Comment: show PM2_Mod PP1_Mod PS2_Mod PS3_Supp PS4_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

Likely pathogenic (Aug 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV005906224.2 First in ClinVar: Apr 13, 2025 Last updated: Oct 25, 2025	Publications: PubMed (2) PubMed: 18803133‚ 9541104 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3 related disorder (ClinVar ID: VCV000407308 /PMID: 9541104 /3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 18803133, 9541104). 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 Method: exome sequencing

Comment:

The p.N755K variant (also known as c.2265C>A), located in coding exon 23 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 2265. The asparagine at codon 755 is replaced by lysine, an amino acid with similar properties. This variant was identified in one or more individuals with features consistent with hypertrophic cardiomyopathy, segregated with disease in at least one family, and was determined to be de novo in at least one individual (Yu B et al. J Med Genet, 1998 Mar;35:183-8; Yu B et al. J Med Genet, 1998 Mar;35:205-10; Rudziski T et al. Kardiol Pol, 2008 Aug;66:821-5; discussion 826-7; Walsh R et al. Genet Med, 2017 02;19:192-203; Gal DB et al. Pediatr Cardiol. 2022 Mar;43(3):616-623; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 755 of the MYBPC3 protein (p.Asn755Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9541100, 9541104, 18803133; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407308). 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: 12386147, 12787675). For these reasons, this variant has been classified as Pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3 related disorder (ClinVar ID: VCV000407308 /PMID: 9541104 /3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 18803133, 9541104). 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
Missense mutations in the central domains of cardiac myosin binding protein-C and their potential contribution to hypertrophic cardiomyopathy.	Pearce A	The Journal of biological chemistry	2024	PMID: 38042491
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
Comprehensive Genetic Testing for Pediatric Hypertrophic Cardiomyopathy Reveals Clinical Management Opportunities and Syndromic Conditions.	Gal DB	Pediatric cardiology	2022	PMID: 34714385
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
Myosin binding protein C: implications for signal-transduction.	Knöll R	Journal of muscle research and cell motility	2012	PMID: 22173300
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.	Jordan DM	American journal of human genetics	2011	PMID: 21310275
Selected mutations in the myosin binding protein C gene in the Polish population of patients with hypertrophic cardiomyopathy.	Rudziński T	Kardiologia polska	2008	PMID: 18803133
What is the value of mutation identification in familial hypertrophic cardiomyopathy?	Yu B	IUBMB life	2004	PMID: 15370892
Cardiac myosin binding protein C: its role in physiology and disease.	Flashman E	Circulation research	2004	PMID: 15166115
Structure, stability and dynamics of the central domain of cardiac myosin binding protein C (MyBP-C): implications for multidomain assembly and causes for cardiomyopathy.	Idowu SM	Journal of molecular biology	2003	PMID: 12787675
Identification of novel interactions between domains of Myosin binding protein-C that are modulated by hypertrophic cardiomyopathy missense mutations.	Moolman-Smook J	Circulation research	2002	PMID: 12386147
Structure-function relationships in myosin binding protein-C: taking off the blinders and collaring hypertrophic cardiomyopathy.	Robbins J	Circulation research	2002	PMID: 12386140
Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.	Yu B	Journal of medical genetics	1998	PMID: 9541104
Counselling issues in familial hypertrophic cardiomyopathy.	Yu B	Journal of medical genetics	1998	PMID: 9541100
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Text-mined citations for rs1060501474 ...

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