VCV000042743.25 - ClinVar

NM_000256.3(MYBPC3):c.3797G>A (p.Cys1266Tyr)

Germline

Classification

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

Uncertain significance
Uncertain significance (7)

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.3797G>A (p.Cys1266Tyr)

Variation ID: 42743 Accession: VCV000042743.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332089 (GRCh38) [ NCBI UCSC ] 11: 47353640 (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	Sep 26, 2017	Feb 15, 2026	Jan 28, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3797G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Cys1266Tyr	missense
NC_000011.10:g.47332089C>T
NC_000011.9:g.47353640C>T
NG_007667.1:g.25614G>A
LRG_386:g.25614G>A
LRG_386t1:c.3797G>A	LRG_386p1:p.Cys1266Tyr

... more HGVS ... less HGVS

Protein change

C1266Y

Other names

Canonical SPDI

NC_000011.10:47332088: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.

Links

ClinGen: CA014925 dbSNP: rs397516041 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	Sep 15, 2025	RCV000505727.8
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 18, 2023	RCV000766384.4
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 28, 2026	RCV000696277.12
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Sep 23, 2021	RCV002477070.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jun 23, 2023	RCV003380402.2

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 (May 31, 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: SCV004814319.1 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

Uncertain significance (Jan 28, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000824829.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 22267749‚ 27532257‚ 28492532‚ 32009526‚ 33782553‚ 37652022 Comment: show This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1266 of the MYBPC3 protein (p.Cys1266Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 32009526, 33782553, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42743). 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. This variant disrupts the p.Cys1266 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. 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 (Sep 23, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002791872.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Jul 23, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208205.6 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: show Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42743; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 27532257, 22267749, 31006259) (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 18, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059269.5 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Comment: show The p.Cys1266Tyr variant in MYBPC3 has been reported in at least 2 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 1 affected relative. (Page 2012 PMID: 22267749, Walsh 2017 PMID: 27532257, Thompson 2021 PMID: 33782553, LMM internal data). It was also identified in 1 individual with a clinical diagnosis of cardiomyopathy with no additional details provided (Pottinger 2020 PMID: 32009526). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 42743) and was absent from large population studies (gnomAD v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting. (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 (Jun 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004087754.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 22267749‚ 27532257‚ 31006259 Comment: show The p.C1266Y variant (also known as c.3797G>A), located in coding exon 33 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3797. The cysteine at codon 1266 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Walsh R et al. Genet. Med., 2017 02;19:192-203; Norrish G et al. Circulation, 2019 Jul;140:184-192). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Uncertain significance (Sep 15, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917819.5 First in ClinVar: Jun 02, 2019 Last updated: Dec 14, 2025	Publications: PubMed (7) PubMed: 22267749‚ 27532257‚ 31006259‚ 32009526‚ 33495596‚ 33782553‚ 37652022 Comment: show Variant summary: MYBPC3 c.3797G>A (p.Cys1266Tyr) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 248458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3797G>A has been observed in individual(s) affected with Hypertrophic Cardiomyopathy (Page_2012, Walsh_2017, Pottinger_2020, Norrish_2019, Thompson_2021, Tadros_2021, McGurk_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22267749, 27532257, 31006259, 32009526, 33495596, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 42743). Based on the evidence outlined above, the variant was classified as 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:

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1266 of the MYBPC3 protein (p.Cys1266Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22267749, 27532257, 32009526, 33782553, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42743). 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. This variant disrupts the p.Cys1266 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. 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:

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42743; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 27532257, 22267749, 31006259)

Comment:

The p.Cys1266Tyr variant in MYBPC3 has been reported in at least 2 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 1 affected relative. (Page 2012 PMID: 22267749, Walsh 2017 PMID: 27532257, Thompson 2021 PMID: 33782553, LMM internal data). It was also identified in 1 individual with a clinical diagnosis of cardiomyopathy with no additional details provided (Pottinger 2020 PMID: 32009526). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 42743) and was absent from large population studies (gnomAD v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting.

Comment:

The p.C1266Y variant (also known as c.3797G>A), located in coding exon 33 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3797. The cysteine at codon 1266 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Walsh R et al. Genet. Med., 2017 02;19:192-203; Norrish G et al. Circulation, 2019 Jul;140:184-192). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Variant summary: MYBPC3 c.3797G>A (p.Cys1266Tyr) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 248458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3797G>A has been observed in individual(s) affected with Hypertrophic Cardiomyopathy (Page_2012, Walsh_2017, Pottinger_2020, Norrish_2019, Thompson_2021, Tadros_2021, McGurk_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22267749, 27532257, 31006259, 32009526, 33495596, 33782553, 37652022). ClinVar contains an entry for this variant (Variation ID: 42743). Based on the evidence outlined above, the variant was classified as 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
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.	Thompson AD	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33782553
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.	Tadros R	Nature genetics	2021	PMID: 33495596
Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants.	Pottinger TD	Journal of the American Heart Association	2020	PMID: 32009526
Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives.	Norrish G	Circulation	2019	PMID: 31006259
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
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.	Page SP	Circulation. Cardiovascular genetics	2012	PMID: 22267749

Text-mined citations for rs397516041 ...

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