Metachondromatosis: genes and variants

Genes linked to Metachondromatosis

• 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.

  11 disease-causing and 28 uncertain variants in PTPN11 are linked to Metachondromatosis.

Where Metachondromatosis variants cluster

• PTPN11 SH2 1 (positions 6–102): 7 of 11 disease-causing changes, 3.9× more than its size predicts.

Known disease-causing variants in Metachondromatosis

Which prediction tools work for Metachondromatosis

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

• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• CATVariant: 82 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 partly in the same places as the Metachondromatosis variants (51 disease-causing).
• Noonan syndrome is also caused by PTPN11 variants; they fall partly in the same places as the Metachondromatosis variants (44 disease-causing).
• Noonan syndrome and Noonan-related syndrome is also caused by PTPN11 variants; they fall partly in the same places as the Metachondromatosis variants (29 disease-causing).
• LEOPARD syndrome 1 is also caused by PTPN11 variants; they fall mostly in different places as the Metachondromatosis variants (16 disease-causing).
• Monogenic short statue is also caused by PTPN11 variants; they fall partly in the same places as the Metachondromatosis variants (6 disease-causing).

Diseases related to Metachondromatosis

• RASopathy, also linked to PTPN11
• Noonan syndrome, also linked to PTPN11
• Noonan syndrome and Noonan-related syndrome, also linked to PTPN11
• Acute myeloid leukemia, also linked to PTPN11
• LEOPARD syndrome 1, also linked to PTPN11
• Juvenile myelomonocytic leukemia, also linked to PTPN11
• Monogenic short statue, also linked to PTPN11
• Male infertility with azoospermia or oligozoospermia due to single gene mutation, also linked to PTPN11
• Microcephaly, also linked to PTPN11
• Noonan syndrome with multiple lentigines, also linked to PTPN11
• Non-immune hydrops fetalis, also linked to PTPN11
• Congenital anomaly of kidney and urinary tract, also linked to PTPN11

Frequently asked questions

Which genes are linked to Metachondromatosis?

In CATVariant, Metachondromatosis is linked to 1 analyzed protein: PTPN11 (Tyrosine-protein phosphatase non-receptor type 11).

How many genetic variants are linked to Metachondromatosis?

54 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 28 are of uncertain significance or have conflicting reports.

Which uncertain variants in Metachondromatosis 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 Metachondromatosis?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.86, based on 11 disease-causing and 11 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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