ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.167T>C (p.Ile56Thr) (rs1052382672)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788007 SCV000927039 likely pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.167T>C (p.Ile56Thr) variant in PTPN11 has been identified in 2 related patients with clinical features of a RASopathy (PS4_Supporting, PP1; Invitae internal data; GTR Lab ID 500031; ClinVar SCV000659038.1). A different pathogenic missense variant (p.Ile56Val) has been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40485). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ile56Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PP1, PM2, PM5, PP2, PP3.
Invitae RCV000531774 SCV000659038 uncertain significance Rasopathy 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 56 of the PTPN11 protein (p.Ile56Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTPN11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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