ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.182A>T (p.Asp61Val) (rs121918461)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000687319 SCV000814882 pathogenic Rasopathy 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 61 of the PTPN11 protein (p.Asp61Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several patients affected with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 14982869, 12717436, 25097206, 18470943, 15928039, 23832011). It has also been observed to be de novo in an individual with clinical features consistent with a PTPN11-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 40496). Experimental studies have shown that this missense change demonstrates hypersensitivity to granulocyte-macrophage colony-stimulating factor leading to sustained phospho-Erk activation (PMID: 17053061, 15644411). The p.Asp61 amino acid residue in PTPN11 has been determined to be clinically significant (PMID: 25039348, 15521065, 11992261, 26242988, 24803665, 27521173, 20112233, 24803665, 11704759, 15273746, 24718990, 26242988, 15987685, 24803665, 16377799, 19835954, 25383899, 28366775, 24628801, 22371576, 27521173, 19008228, 20651068, 19927903). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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