Noonan syndrome 2

Summary

Noonan syndrome 2 (MONDO:0011531) is a disease caused by LZTR1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LZTR1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 176

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 2
Mondo ID	MONDO:0011531
MeSH	C548081
OMIM	605275
DOID	DOID:0060580
NCIT	C176930
UMLS	C1854469
MedGen	344290
GARD	0010698
Is cancer (heuristic)	no

Also known as: autosomal recessive Noonan syndrome · Noonan syndrome 2 · Noonan syndrome autosomal recessive · Noonan syndrome type 2 · NS2

Data availability: 176 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 2

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

176 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 34 conflicting classifications of pathogenicity, 27 pathogenic/likely pathogenic, 20 likely pathogenic, 18 pathogenic, 11 benign/likely benign, 2 likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
143931	NM_006767.4(LZTR1):c.27del (p.Gln10fs)	LOC130067016	Pathogenic	criteria provided, multiple submitters, no conflicts
3375822	NM_006767.4(LZTR1):c.104C>A (p.Ser35Ter)	LOC130067016	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372684	NM_006767.4(LZTR1):c.27dup (p.Gln10fs)	LOC130067016	Pathogenic	reviewed by expert panel
101034	NM_006767.4(LZTR1):c.264-13G>A	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101037	NM_006767.4(LZTR1):c.2348_2351del (p.Thr783fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101038	NM_006767.4(LZTR1):c.1397G>A (p.Arg466Gln)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073645	NM_006767.4(LZTR1):c.890_891del (p.Tyr297fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162325	NM_006767.4(LZTR1):c.1605C>A (p.Tyr535Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319829	NM_006767.4(LZTR1):c.1310G>A (p.Trp437Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321013	NM_006767.4(LZTR1):c.485G>A (p.Trp162Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1409252	NM_006767.4(LZTR1):c.2244C>G (p.Tyr748Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453718	NM_006767.4(LZTR1):c.465C>G (p.Tyr155Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456304	NM_006767.4(LZTR1):c.1602del (p.Lys534fs)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457076	NM_006767.4(LZTR1):c.2284C>T (p.Gln762Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1683643	NM_006767.4(LZTR1):c.1078A>T (p.Lys360Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1738993	NM_006767.4(LZTR1):c.423T>G (p.Tyr141Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1773190	NM_006767.4(LZTR1):c.1462G>T (p.Glu488Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1776399	NM_006767.4(LZTR1):c.1611del (p.Gly539fs)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1784239	NM_006767.4(LZTR1):c.2001_2002del (p.Cys667_Asp668delinsTer)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1784418	NM_006767.4(LZTR1):c.2011_2012del (p.Leu671fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1785966	NM_006767.4(LZTR1):c.2104G>T (p.Glu702Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
1992330	NM_006767.4(LZTR1):c.844C>T (p.Gln282Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2153109	NM_006767.4(LZTR1):c.400+1G>A	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627558	NM_006767.4(LZTR1):c.1676T>A (p.Leu559Ter)	LZTR1	Pathogenic	criteria provided, single submitter
2899790	NM_006767.4(LZTR1):c.1321C>T (p.Gln441Ter)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts
3238130	NM_006767.4(LZTR1):c.1785+2T>C	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376218	NM_006767.4(LZTR1):c.309C>A (p.Cys103Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376752	NM_006767.4(LZTR1):c.494G>A (p.Trp165Ter)	LZTR1	Pathogenic	criteria provided, single submitter
3382743	NM_006767.4(LZTR1):c.855C>A (p.Tyr285Ter)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3624754	NM_006767.4(LZTR1):c.842dup (p.Gln282fs)	LZTR1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LZTR1	Definitive	Autosomal dominant	Noonan syndrome 10	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	gencc,clinvar
THAP7	HGNC:23190	ENSG00000184436	Q9BT49	THAP domain-containing protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
THAP7	THAP domain-containing protein 7	Chromatin-associated, histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressors.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
THAP7	Transcription factor	no		THAP_Znf, THAP7

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	2
pituitary gland	2
sural nerve	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
THAP7	283	ubiquitous	marker	adenohypophysis, pituitary gland, right testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THAP7	1,696
LZTR1	1,562

Intra-cohort edges

A	B	Sources
LZTR1	THAP7	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LZTR1	Q8N653	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
THAP7	Q9BT49	70.89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of Ras protein signal transduction	1	337.0×	0.018	LZTR1
chromatin organization	1	49.6×	0.060	THAP7
protein ubiquitination	1	20.7×	0.075	LZTR1
regulation of DNA-templated transcription	1	15.8×	0.075	THAP7
negative regulation of DNA-templated transcription	1	15.8×	0.075	THAP7
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	THAP7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LZTR1	0	0
THAP7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LZTR1, THAP7

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LZTR1	0	—
THAP7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.