ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.392A>G (p.Lys131Arg) (rs397516805)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621552 SCV000736206 uncertain significance Cardiovascular phenotype 2016-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678902 SCV000805102 uncertain significance Noonan syndrome 2017-03-08 no assertion criteria provided clinical testing
GeneDx RCV000680297 SCV000514316 likely benign not provided 2018-05-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ITMI RCV000037646 SCV000086117 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000654924 SCV000776830 uncertain significance Rasopathy 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 131 of the PTPN11 protein (p.Lys131Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs397516805, ExAC 0.05%). This variant has not been reported in the literature in individuals with PTPN11-related disease. ClinVar contains an entry for this variant (Variation ID: 44607). 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: "Deleterious"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037646 SCV000061308 uncertain significance not specified 2011-06-12 criteria provided, single submitter clinical testing The Lys131Arg variant in PTPN11 has been reported in the literature in one Chine se individual with clinical features of Noonan syndrome (Chan 2006). This varian t was identified in that individual's mother; however clinical features for the mother were not provided. In addition, this variant has been detected by our lab oratory in one Asian proband who also has a pathogenic MEK1 variant. The Lys131 residue is highly conserved across mammals and lower species and computational a nalyses (PolyPhen2, SIFT, AlignGVGD) suggest that the Lys131Arg variant may impa ct the normal function of PTPN11. Given this information, we are unable to make a conclusive determination as to whether this variant is responsible for the cli nical features observed in this individual.

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