Juvenile myelomonocytic leukemia: genes and variants

Genes linked to Juvenile myelomonocytic leukemia

• 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.

  5 disease-causing and 27 uncertain variants in PTPN11 are linked to Juvenile myelomonocytic leukemia.

• NF1: Neurofibromin

  It accelerates conversion of active RAS-GTP to inactive RAS-GDP and therefore restrains RAS-MAPK signaling. Loss-of-function variants cause neurofibromatosis type 1 with neurofibromas, pigmentary features, learning difficulties, and increased tumor risk.

  2 disease-causing and 70 uncertain variants in NF1 are linked to Juvenile myelomonocytic leukemia.

• 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 32 uncertain variants in CBL are linked to Juvenile myelomonocytic leukemia.

• 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.

  0 disease-causing and 0 uncertain variants in NRAS are linked to Juvenile myelomonocytic leukemia.

• 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.

  0 disease-causing and 0 uncertain variants in KRAS are linked to Juvenile myelomonocytic leukemia.

Weakly linked (only a few uncertain records): ASXL1.

Where Juvenile myelomonocytic leukemia variants cluster

• PTPN11 Tyrosine-protein phosphatase (positions 247–517): 4 of 5 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Juvenile myelomonocytic leukemia

Which prediction tools work for Juvenile myelomonocytic leukemia

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

• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 79 out of 100
• PolyPhen-2: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• RASopathy is also caused by PTPN11 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (51 disease-causing).
• Noonan syndrome is also caused by PTPN11 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (44 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (29 disease-causing).
• LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (16 disease-causing).
• Metachondromatosis is also caused by PTPN11 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (11 disease-causing).
• Neurofibromatosis is also caused by NF1 variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (51 disease-causing).
• RASopathy is also caused by CBL variants; they fall mostly in different places as the Juvenile myelomonocytic leukemia variants (8 disease-causing).

Diseases related to Juvenile myelomonocytic leukemia

• RASopathy, also linked to CBL, KRAS, NRAS and PTPN11
• Noonan syndrome, also linked to CBL, KRAS, NRAS and PTPN11
• Noonan syndrome and Noonan-related syndrome, also linked to CBL, KRAS, NRAS and PTPN11
• Acute myeloid leukemia, also linked to KRAS, NRAS and PTPN11
• Cardiofaciocutaneous syndrome, also linked to KRAS and NRAS
• Autoimmune lymphoproliferative syndrome, also linked to KRAS and NRAS
• Colorectal cancer, also linked to KRAS and NRAS
• Vascular malformation, also linked to KRAS and NRAS
• Linear nevus sebaceous syndrome, also linked to KRAS and NRAS
• Melanoma, also linked to NF1 and NRAS
• Hypertrophic cardiomyopathy, also linked to NRAS
• Neurofibromatosis, also linked to NF1

Frequently asked questions

Which genes are linked to Juvenile myelomonocytic leukemia?

In CATVariant, Juvenile myelomonocytic leukemia is linked to 5 analyzed proteins: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11), NF1 (Neurofibromin), CBL (E3 ubiquitin-protein ligase CBL), NRAS (GTPase NRas) and KRAS (GTPase KRas).

How many genetic variants are linked to Juvenile myelomonocytic leukemia?

159 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 130 are of uncertain significance or have conflicting reports.

Which uncertain variants in Juvenile myelomonocytic leukemia 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 Juvenile myelomonocytic leukemia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.79, based on 8 disease-causing and 251 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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