LZTR1

Chr 22ADAR

leucine zipper like post translational regulator 1

Also known as: BTBD29, LZTR-1, NS10, NS2, SWNTS2

NCBI Gene: 8216ENSG00000099949UniProt: Q8N653

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]

Primary Disease Associations & Inheritance

{Schwannomatosis-2, susceptibility to}MIM #615670
AD
Noonan syndrome 10MIM #616564
AD
Noonan syndrome 2MIM #605275
AR
UniProtGlioma
UniProtSchwannomatosis 2
700
ClinVar variants
127
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— LZTR1
🧬
Gene-Disease Validity (ClinGen)
Noonan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
127 Pathogenic / Likely Pathogenic· 362 VUS of 700 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.99LOEUF
pLI 0.000
Z-score -8.05
OE 2.28 (1.75–1.99)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.58Z-score
OE missense 0.93 (0.86–1.00)
503 obs / 540.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.2.28 (1.75–1.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.86–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 105 / 46.0Missense obs/exp: 503 / 540.7Syn Z: -0.91

ClinVar Variant Classifications

700 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic98
Likely Pathogenic29
VUS362
Likely Benign202
Conflicting9
98
Pathogenic
29
Likely Pathogenic
362
VUS
202
Likely Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
61
0
37
0
98
Likely Pathogenic
25
2
2
0
29
VUS
8
289
61
4
362
Likely Benign
0
1
122
79
202
Benign
0
0
0
0
0
Conflicting
—9
Total9429222283700

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LZTR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

LZTR1-related Noonan syndrome (monoallelic)

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

LZTR1-related Noonan syndrome (biallelic)

strong
ARUndeterminedUncertain
Dev. Disorders
G2P ↗

LZTR1-related breast cancer, susceptibility to

moderate
ADUndeterminedUncertain
Cancer
G2P ↗

LZTR1-related schwannomatosis

definitive
ADLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Schwannomatosis-2, susceptibility to}

MIM #615670

Molecular basis of disorder known

Autosomal dominant

Noonan syndrome 10

MIM #616564

Molecular basis of disorder known

Autosomal dominant

Noonan syndrome 2

MIM #605275

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — LZTR1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis.
Tamura R·Int J Mol Sci
2021Review
Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation.
Plotkin SR et al.·Genet Med
2022
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma.
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu et al.·Cell
2017
Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.
Johnston JJ et al.·Genet Med
2018
Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.
Pagnamenta AT et al.·Clin Genet
2019Case report
LZTR1 is a regulator of RAS ubiquitination and signaling.
Bigenzahn JW et al.·Science
2018
LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis.
Farncombe KM et al.·BMC Med Genomics
2022Review
Genetics of short stature.
Nicolae R et al.·Curr Opin Pediatr
2025Review
Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features.
Uliana V et al.·Genes (Basel)
2024Review
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.
Yamamoto GL et al.·J Med Genet
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING
NCT06489067University of Bari Aldo MoroStarted 2024-01-15

External Resources

Links to major genomics databases and tools