Noonan syndrome and Noonan-related syndrome: genes and variants

Genes linked to Noonan syndrome and Noonan-related syndrome

• PTPN11: Tyrosine-protein phosphatase non-receptor type 11

  Its SHP2 phosphatase activity promotes RAS-MAPK signaling downstream of many receptor tyrosine kinases and cytokine receptors. Germline dysregulating variants cause Noonan-spectrum disorders, while somatic activating variants drive juvenile myelomonocytic leukemia and other cancers.

  29 disease-causing and 9 uncertain variants in PTPN11 are linked to Noonan syndrome and Noonan-related syndrome.

• BRAF: Serine/threonine-protein kinase B-raf

  It relays activated RAS signals through MEK and ERK to control proliferation, differentiation, and survival. Activating variants, especially V600E, drive melanoma and several other cancers and create sensitivity to pathway-directed therapies.

  10 disease-causing and 7 uncertain variants in BRAF are linked to Noonan syndrome and Noonan-related syndrome.

• SOS1: Son of sevenless homolog 1

  It activates RAS by exchanging GDP for GTP downstream of receptor tyrosine kinases. Germline activating variants are a common cause of Noonan syndrome, while excessive SOS1-RAS signaling can contribute to cancer.

  9 disease-causing and 20 uncertain variants in SOS1 are linked to Noonan syndrome and Noonan-related syndrome.

• RIT1: GTP-binding protein Rit1

  It transmits growth and stress signals through RAS-MAPK and related pathways and is important in cardiovascular and nervous-system development. Germline activating variants cause Noonan syndrome, often with a high frequency of hypertrophic cardiomyopathy.

  9 disease-causing and 7 uncertain variants in RIT1 are linked to Noonan syndrome and Noonan-related syndrome.

• RAF1: RAF proto-oncogene serine/threonine-protein kinase

  It relays activated RAS signals to MEK and ERK and also participates in survival and developmental pathways. Germline activating variants cause Noonan syndrome and related RASopathies, while oncogenic activation contributes to selected cancers.

  4 disease-causing and 11 uncertain variants in RAF1 are linked to Noonan syndrome and Noonan-related syndrome.

• HRAS: GTPase HRas

  Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome.

  3 disease-causing and 3 uncertain variants in HRAS are linked to Noonan syndrome and Noonan-related syndrome.

• CBL: E3 ubiquitin-protein ligase CBL

  It limits receptor-tyrosine-kinase signaling by ubiquitinating activated receptors and promoting their internalization and degradation. Germline or somatic pathogenic variants can prolong RAS-MAPK signaling and cause Noonan-like developmental disease or myeloid malignancy.

  2 disease-causing and 22 uncertain variants in CBL are linked to Noonan syndrome and Noonan-related syndrome.

• NRAS: GTPase NRas

  Its active GTP-bound state drives RAF-MEK-ERK and PI3K signaling downstream of growth-factor receptors. Somatic activating variants are common drivers of melanoma, leukemia, and other cancers, while germline activating variants can cause Noonan syndrome.

  2 disease-causing and 2 uncertain variants in NRAS are linked to Noonan syndrome and Noonan-related syndrome.

• MAP2K1: Dual specificity mitogen-activated protein kinase kinase 1

  It phosphorylates ERK1 and ERK2 downstream of RAF and thereby propagates RAS-MAPK growth and developmental signals. Activating somatic variants occur in several cancers, while germline activating variants can cause cardio-facio-cutaneous syndrome and related RASopathies.

  1 disease-causing and 4 uncertain variants in MAP2K1 are linked to Noonan syndrome and Noonan-related syndrome.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  1 disease-causing and 1 uncertain variants in KRAS are linked to Noonan syndrome and Noonan-related syndrome.

• SOS2: Son of sevenless homolog 2

  It activates RAS by catalyzing GDP-GTP exchange downstream of growth-factor receptors. Germline activating variants cause Noonan syndrome, generally through increased RAS-MAPK signaling.

  0 disease-causing and 3 uncertain variants in SOS2 are linked to Noonan syndrome and Noonan-related syndrome.

• MAP2K2: Dual specificity mitogen-activated protein kinase kinase 2

  It works with MEK1 to activate ERK signaling downstream of RAS and RAF. Germline activating variants can cause cardio-facio-cutaneous syndrome, while acquired activation can support oncogenic MAPK signaling and drug resistance.

  0 disease-causing and 8 uncertain variants in MAP2K2 are linked to Noonan syndrome and Noonan-related syndrome.

Where Noonan syndrome and Noonan-related syndrome variants cluster

• PTPN11 SH2 1 (positions 6–102): 16 of 29 disease-causing changes, 3.4× more than its size predicts.
• BRAF Phorbol-ester/DAG-type (positions 234–280): 4 of 10 disease-causing changes, 6.5× more than its size predicts.
• BRAF Protein kinase (positions 457–717): 6 of 10 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Noonan syndrome and Noonan-related syndrome

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Which prediction tools work for Noonan syndrome and Noonan-related syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 84 out of 100
• EVE: 75 out of 100
• SIFT: 74 out of 100
• phyloP: 72 out of 100

Same protein, different disease

• RASopathy is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (51 disease-causing).
• Noonan syndrome is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (44 disease-causing).
• LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (16 disease-causing).
• Metachondromatosis is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (11 disease-causing).
• Monogenic short statue is also caused by PTPN11 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (6 disease-causing).
• RASopathy is also caused by BRAF variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (36 disease-causing).
• Cardio-facio-cutaneous syndrome is also caused by BRAF variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (26 disease-causing).
• Cardiofaciocutaneous syndrome is also caused by BRAF variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (17 disease-causing).
• Noonan syndrome is also caused by BRAF variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (11 disease-causing).
• Non-small cell lung carcinoma is also caused by BRAF variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (9 disease-causing).
• Noonan syndrome is also caused by SOS1 variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (30 disease-causing).
• RASopathy is also caused by SOS1 variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (22 disease-causing).
• Fibromatosis, gingival, 1 is also caused by SOS1 variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (4 disease-causing).
• Noonan syndrome is also caused by RIT1 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (22 disease-causing).
• RASopathy is also caused by RIT1 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (5 disease-causing).
• RASopathy is also caused by RAF1 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (28 disease-causing).
• Noonan syndrome is also caused by RAF1 variants; they fall in the same places as the Noonan syndrome and Noonan-related syndrome variants (14 disease-causing).
• Dilated cardiomyopathy 1NN is also caused by RAF1 variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (5 disease-causing).
• LEOPARD syndrome 1 is also caused by RAF1 variants; they fall in the same places as the Noonan syndrome and Noonan-related syndrome variants (4 disease-causing).
• Costello syndrome is also caused by HRAS variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (15 disease-causing).
• RASopathy is also caused by HRAS variants; they fall mostly in different places as the Noonan syndrome and Noonan-related syndrome variants (6 disease-causing).
• Large congenital melanocytic nevus is also caused by HRAS variants; they fall partly in the same places as the Noonan syndrome and Noonan-related syndrome variants (5 disease-causing).

Diseases related to Noonan syndrome and Noonan-related syndrome

• RASopathy, also linked to BRAF, CBL, HRAS, KRAS and 8 more
• Noonan syndrome, also linked to BRAF, CBL, HRAS, KRAS and 8 more
• Hypertrophic cardiomyopathy, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
• Cardiofaciocutaneous syndrome, also linked to BRAF, KRAS, MAP2K1, MAP2K2 and 1 more
• Costello syndrome, also linked to BRAF, HRAS, MAP2K1, MAP2K2 and 1 more
• Cardio-facio-cutaneous syndrome, also linked to BRAF, KRAS, MAP2K1 and MAP2K2
• Vascular malformation, also linked to BRAF, KRAS, MAP2K1 and NRAS
• Juvenile myelomonocytic leukemia, also linked to CBL, KRAS, NRAS and PTPN11
• Melanoma, also linked to BRAF, MAP2K1, MAP2K2 and NRAS
• Acute myeloid leukemia, also linked to KRAS, NRAS and PTPN11
• LEOPARD syndrome 1, also linked to BRAF, PTPN11 and RAF1
• Colorectal cancer, also linked to BRAF, KRAS and NRAS

Frequently asked questions

Which genes are linked to Noonan syndrome and Noonan-related syndrome?

In CATVariant, Noonan syndrome and Noonan-related syndrome is linked to 12 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), BRAF (Serine/threonine-protein kinase B-raf), SOS1 (Son of sevenless homolog 1), RIT1 (GTP-binding protein Rit1), RAF1 (RAF proto-oncogene serine/threonine-protein kinase), HRAS (GTPase HRas) and 6 more.

How many genetic variants are linked to Noonan syndrome and Noonan-related syndrome?

213 variants: 70 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 97 are of uncertain significance or have conflicting reports.

Which uncertain variants in Noonan syndrome and Noonan-related syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Noonan syndrome and Noonan-related syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 51 disease-causing and 51 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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