LZTR1

protein-coding

leucine zipper like post translational regulator 1, the group of BTB domain containing

Gene summary

This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006767.4

Inheritance

AD, AR

ClinVar variants

P:955U:2151B:872

Top phenotype

Schwannomatosis 2; Noonan syndrome 10; Noonan syndrome 2

gnomAD constraint

pLI —, LoF o/e 2.28

Max pathogenic AF

—

Genomic locus

chr22:20,982,269-20,999,032

External References & Databases

Ensembl (ENSG00000099949)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

LZTR1-related schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014299

Submitter: ClinGen

LZTR1 was first reported in relation to autosomal dominant Schwannomatosis (SWN) in 2014 (Piotrowski et al. 2014, PMID: 24362817). SWN is a rare, inherited tumor syndrome that leads to an increased risk for Schwannoma development. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found other disease entities associated with this gene (Noonan Syndrome 10 - AD [MONDO:0014693] and Noonan Syndrome 2 – AR [OMIM:605275]) that were split from this curation. Nine variants (nonsense, splice site, frameshift, and missense) that have been reported in 9 probands described in 2 publications (PMIDs: 24362817 and 25008767) and one case-control study (PMID: 35391499) are included in this curation. The mechanism of pathogenicity is reported to be heterozygous LOF. Pathogenic loss-of-function variants are not uncommon in the general population, and the expected penetrance of SWN is extremely low in individuals with no family history (<1%)(PMID: 35361920 ). This gene-disease relationship is also supported by experimental evidence (expression studies) (PMIDs: 25335493). Heterozygous loss of LZTR1 alone is not sufficient to trigger the development of schwannomas. Development of LZTR1-related schwannomatosis is dependent on additional somatic mutational events known as the 3-step/4-hit model that causes biallelic loss of function of both LZTR1 and NF2.PMID: 24362817). In summary, there is definitive evidence supporting the relationship between LZTR1 and autosomal dominant Schwannomatosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was curated on 08/21/2025 by the Hereditary Cancer GCEP (SOP Version 11).

Noonan syndrome 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014693

Submitter: Labcorp Genetics (formerly Invitae)

LZTR1-related schwannomatosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014299

Submitter: Genomics England PanelApp

Noonan syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011531

Submitter: Genomics England PanelApp

Noonan syndrome 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014693

Submitter: Genomics England PanelApp

LZTR1-related schwannomatosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014299

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

LZTR1 was associated with autosomal dominant Noonan syndrome by Chen et al. in 2014. Evidence supporting this gene-disease relationship includes case-level data and an animal model. At least 10 unique variants have been reported in humans with Noonan syndrome. In addition to those described in the literature, six variants with confirmed de novo inheritance and one variant with unconfirmed de novo inheritance have been identified at GeneDx in individuals with features consistent with a RASopathy (SCV000330730, SCV000491887, SCV000619636, SCV000778848, SCV000778849, SCV000778850, SCV000568857). Several missense and other non-LOF variants have been identified to segregate in a dominant manner, while heterozygous LOF variants have been found in unaffected carriers in families with recessive Noonan syndrome, therefore, the suspected mechanism of disease in LZTR1 is dominant-negative. Further functional evidence is required to solidify this mechanism (Johnston et al., 2018). In summary, LZTR1 is definitively associated with autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, LZTR1 has also been classified as strong in relation to autosomal recessive Noonan syndrome. Additionally, the ClinGen RASopathy Expert Panel has assessed LZTR1 for associations with both autosomal dominant and recessive forms of Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, and Cardiofaciocutaneous syndrome, but no evidence was reported. This classification was approved by the ClinGen RASopathy Expert Panel on 4/23/2020.

LZTR1-related schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014299

Submitter: Ambry Genetics

Noonan syndrome 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014693

Submitter: G2P

breast cancerMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: G2P

schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008075

Submitter: G2P

Noonan syndrome 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014693

Submitter: Ambry Genetics

Noonan syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011531

Submitter: Ambry Genetics

Noonan syndrome 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014693

Submitter: G2P

Noonan syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018997

Submitter: ClinGen

LZTR1 was first reported in relation to autosomal recessive Noonan syndrome in 2018 (Johnston et al., PMID: 29469822). The split curation for autosomal dominant Noonan syndrome has been curated separately. 27 variants (missense, nonsense, frameshift, and splicing) that have been reported in 18 probands in 4 publications (PMIDs: 29469822, 29959388, 30859559, 31182298) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by interaction between LZTR1 and the RAF1/SHOC2/PPP1CB complex (PMIDs: 30368668). In summary, there is definitive evidence supporting the relationship between LZTR1 and autosomal recessive Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, LZTR1 has also been classified as definitive in relation to autosomal dominant Noonan syndrome. Additionally, the ClinGen RASopathy Expert Panel has assessed LZTR1 for associations with both autosomal dominant and recessive forms of Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, and Cardiofaciocutaneous syndrome, but no evidence was reported. This gene-disease pair was originally evaluated by the RASopathy GCEP on July 24, 2018. It was re-evaluated on August 27, 2020 (SOP Version 9). As a result of this reevaluation, the classification increased from Limited to Definitive with the addition of additional published cases (PMIDs: 29959388, 30859559, 31182298) and experimental evidence (PMID: 30368668).

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Clinical Genomic Database (CGD)

Schwannomatosis 2; Noonan syndrome 10; Noonan syndrome 2AD/AR

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Oncologic

Intervention: Cardiovascular; Hematologic; Oncologic

Rationale: Individuals with Schwannomatosis are susceptible to schwannomas, and knowledge may allow early management; Individuals with Noonan syndrome may benefit from surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis or hypertrophic cardiomyopathy); Noonan syndrome can can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial; Noonan syndrome can also include schwannomatosis as well as predisposition to other types of cancer, and knowledge may allow early management

Refs: 24362817; 25480913; 25795793; 29469822; 30368668

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LZTR1 variants in ClinVar

40 Conditions Cataloged

Cardiovascular phenotypeTotal: 3259

Hereditary cancer-predisposing syndromeTotal: 3259

not providedTotal: 3253

LZTR1-related schwannomatosisTotal: 502

not specifiedTotal: 392

Noonan syndrome 10Total: 247

LZTR1-related disorderTotal: 237

Noonan syndrome 2Total: 229

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006767.4. 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		6 clinvar	35 clinvar	785 clinvar	5 clinvar	831
missense	6 clinvar	86 clinvar	2057 clinvar	79 clinvar		2228
nonsense	126 clinvar	71 clinvar	10 clinvar			207
start loss	1 clinvar	3 clinvar				4
frameshift	355 clinvar	122 clinvar	29 clinvar			506
splice donor/acceptor (+/-2bp)	12 clinvar	167 clinvar	20 clinvar	3 clinvar		202
Total	500	455	2151	867	5	3978

Highest pathogenic variant AF is 0.00009299442

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006767.4	RefSeq	NP_006758.2	21	MANE Select
ENST00000646124.2	Ensembl	ENSP00000496779.1	21	MANE Select
ENST00000414985.5	Ensembl	ENSP00000397247.1	4	Standard
ENST00000415354.6	Ensembl	ENSP00000393765.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
anatomical structure morphogenesis

Molecular Function

DNA-binding transcription factor activity

Cellular Component

Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000215739
Coding exons: 21
Length: 19577
Individuals with no LoFs: 125362
Homozygous LoFs: 0
Heterozygous LoFs: 386
Defined: 125748
p: 0.00154

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.577	503	541	0.930	0.0000351	5428
Missense (PolyPhen)		163	202.82	0.80368		2073
Synonymous	-0.907	256	238	1.07	0.0000170	1622
Loss of Function	-8.05	105	46.0	2.28	0.00000232	485

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0016	notable
Latino/Admixed American	0.0013	0.0013	notable
Ashkenazi Jewish	0.00073	0.00069	rare
East Asian	0.0018	0.0018	notable
Finnish	0.0040	0.0039	notable
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.0016	0.0016	notable
Other	0.0025	0.0024	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcriptional regulator that may play a crucial role in embryogenesis.;
Disease: DISEASE: Schwannomatosis 2 (SWNTS2) [MIM:615670]: A cancer predisposition syndrome in which patients develop multiple non- vestibular schwannomas, benign neoplasms that arise from Schwann cells of the cranial, peripheral, and autonomic nerves. {ECO:0000269|PubMed:24362817}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 10 (NS10) [MIM:616564]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:25795793}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.982
RVIS EVS: -2.68
RVIS percentile EVS: 0.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium