ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.181G>C (p.Asp61His) (rs397507510)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033462 SCV000057367 pathogenic not provided 2018-01-15 criteria provided, single submitter clinical testing The D61H pathogenic variant in the PTPN11 gene has been reported previously as de novo and in association with Noonan syndrome (Houweling et al., 2010). This variant is not observed in large population cohorts (Lek et al., 2016). D61H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. It lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (D61N/G/A) and nearby residues (I56V, N58H/D/K, T59A, G60C/S/A, Y62D/N/C, Y63C) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000589874 SCV000698064 pathogenic Noonan syndrome 3 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.181G>C (p.Asp61His) variant involves the alteration of a conserved nucleotide located within the interface of the amino-terminal SH2 (N-SH2) and catalytic (PTP) domains. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121392 control chromosomes while it was reported in several Noonan Syndrome patients. In one of these patients, the variant proved to be de novo, strongly supporting a pathogenic impact. Furthermore, mutations affecting the same codon Asp61Ala, Asp61Asn, Asp61Gly are listed in databases (HGMD, ClinVar) as pathogenic indicating the variant to be located in a mutational hotspot and the clinical relevance of the Asp61 residue. Considering all evidence, the variant was classified as pathogenic.

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