HEY1
protein-codinghes related family bHLH transcription factor with YRPW motif 1, the group of Basic helix-loop-helix proteins
Gene summary
This gene encodes a nuclear protein belonging to the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcriptional repressors. Expression of this gene is induced by the Notch and c-Jun signal transduction pathways. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*HEY1* was first reported in relation to autosomal dominant congenital heart disease in 2016 (Sicko et al., PMID: 27788187). Three individuals with CHD were identified with CNVs (2 gross duplications and 1 gross deletion), however these CNVs encompass multiple genes near the transcriptional repressor *HEY1*, and thus were not scored (PMID: 27788187). A missense variant was reported in 2 individuals of a family with CHD, however functional assay showed no effect of the variant on transcriptional activity (PMID: 35737725). This gene-disease relationship is supported by evidence of *Hey1* expression exclusively in the atria of the embryonic mouse heart and protein interaction studies with GATA proteins (PMIDs: 10415358, 15485867). No apparent heart defects were observed in the *Hey1* knockout mouse but was seen in two double knockout mouse models (*Hey1/2* and *Hey1/L*) suggesting that the Hey proteins play partially redundant roles during cardiac development (PMIDs: 15107403, 17303760). In summary, the evidence supporting the relationship between *HEY1* and autosomal dominant congenital heart disease has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *HEY1* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 6th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HEY1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012258.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 1 | 8 | |||
| missense | 36 | 1 | 1 | 38 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 36 | 8 | 2 | 46 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036390.3 | 5 | MANE Select | |
| Ensembl | ENSP00000346761.3 | 5 | MANE Select | |
| RefSeq | NP_001035798.1 | 5 | Standard | |
| RefSeq | NP_001269780.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Breast cancer - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Human papillomavirus infection - Homo sapiens (human)
- Heart Development
- Signaling by NOTCH1
Biological Process
- negative regulation of transcription by RNA polymerase II
- angiogenesis
- blood vessel development
- pulmonary valve morphogenesis
- atrioventricular valve formation
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- transcription corepressor activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000337919
- Coding exons
- 5
- Length
- 3854
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125748
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.504 | 160 | 179 | 0.894 | 0.00000807 | 1936 |
| Missense (PolyPhen) | 43 | 69.719 | 0.61676 | 814 | ||
| Synonymous | -0.837 | 91 | 81.4 | 1.12 | 0.00000389 | 676 |
| Loss of Function | 2.03 | 4 | 11.4 | 0.351 | 5.12e-7 | 130 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000030 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (PubMed:11095750). Downstream effector of Notch signaling required for cardiovascular development. Specifically required for the Notch-induced endocardial epithelial to mesenchymal transition, which is itself criticial for cardiac valve and septum development. May be required in conjunction with HEY2 to specify arterial cell fate or identity. Promotes maintenance of neuronal precursor cells and glial versus neuronal fate specification. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6 and by the neuronal bHLH factors ASCL1/MASH1 and NEUROD4/MATH3 (PubMed:15485867). Involved in the regulation of liver cancer cells self-renewal (PubMed:25985737). {ECO:0000250|UniProtKB:Q9WV93, ECO:0000269|PubMed:11095750, ECO:0000269|PubMed:15485867, ECO:0000269|PubMed:25985737}.;
Recessive Scores
- pRec
- 0.234
Intolerance Scores
- LoFtool
- 0.426
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.35
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.441
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |