MYZAP
protein-codingmyocardial zonula adherens protein
Gene summary
This gene encodes a protein that is abundantly expressed in cardiac tissue. The encoded protein localizes to intercalated discs in cardiomyocytes and functions as an activator of Rho-dependent serum-response factor signaling. Alternative splicing results in multiple transcript variants. Readthrough transcription also exists between this gene and the neighboring downstream gene POLR2M (polymerase (RNA) II (DNA directed) polypeptide M) and is represented with GeneID: 145781. [provided by RefSeq, Mar 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~93.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0971175
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0971175
Submitter: ClinGen
MYZAP was evaluated for autosomal recessive (AR) dilated cardiomyopathy (DCM). MYZAP is an intercalated disc (ID) protein that is required to maintain cardiac function. MYZAP is strongly expressed in the heart and localizes to the ID. At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene. At least 5 variants (all predicted or proven null) have been reported in humans with DCM. Two Spanish sibs with compound heterozygous LOF variants (one canonical splice donor and one novel nonsense) and DCM diagnosed in their 30’s. Western blot showed low expression of the splice variant and immunofluorescence testing showed abnormal subcellular localization of the nonsense variant (Ochoa et. al, 2024, PMID: 38436102). Two Slovenian siblings with severe, early-onset DCM and a novel homozygous truncating MYZAP variant. IHC and Western blot showed complete absence of MYZAP protein in the proband’s sample (Maver et. al, 2022, PMID: 35840178). Two Finnish families with two different homozygous truncating variants and a total of 4 individuals with confirmed DCM. Myocardium samples showed loss of myzap-staining compared to controls (Helio et. al, 2021, PMID: 34899865). In addition, these gene-disease assertion is supported by expression studies and animal models. MYZAP KO zebrafish developed cardiomyopathy with pericardial edema and loss of contractility with normal morphology and severe skeletal muscle dysfunction (Seeger et. al, 2010, PMID: 20093627). In summary, there is moderate evidence to support this gene-disease relationship. more evidence is needed to establish the relationship between MYZAP and AR DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 08/23/2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: The condition involves variable-onset dilated cardiomyopathy, including arrhythmias, and early diagnosis may allow medical and surgical interventions; cardiac transplantation has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYZAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001018100.5. 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 | 0 | |||||
| missense | 82 | 82 | ||||
| nonsense | 2 | 2 | 2 | 6 | ||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 4 | 84 | 0 | 0 | 91 |
Highest pathogenic variant AF is 0.00004356176
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001018110.1 | 13 | MANE Select | |
| Ensembl | ENSP00000267853.5 | 13 | MANE Select | |
| RefSeq | NP_689664.3 | 12 | Standard | |
| Ensembl | ENSP00000369939.4 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| myzap | Danio rerio | Structure: atrium Quality: decreased functionality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- intracellular signal transduction
Molecular Function
- protein binding
Cellular Component
- Z disc
- cell junction
- cortical actin cytoskeleton
- extrinsic component of cytoplasmic side of plasma membrane
- I band
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000267853
- Coding exons
- 13
- Length
- 93424
- Individuals with no LoFs
- 125625
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 123
- Defined
- 125748
- p
- 0.000489
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.718 | 265 | 234 | 1.13 | 0.0000120 | 3039 |
| Missense (PolyPhen) | 69 | 68.345 | 1.0096 | 882 | ||
| Synonymous | -2.91 | 121 | 86.6 | 1.40 | 0.00000452 | 838 |
| Loss of Function | 0.526 | 27 | 30.1 | 0.897 | 0.00000160 | 360 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.0020 | 0.0015 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00090 | 0.00087 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.00033 | 0.00033 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in cellular signaling via Rho-related GTP- binding proteins and subsequent activation of transcription factor SRF (By similarity). Targets TJP1 to cell junctions. In cortical neurons, may play a role in glutaminergic signal transduction through interaction with the NMDA receptor subunit GRIN1 (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.102
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |