ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1226G>C (p.Gly409Ala) (rs201247699)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037608 SCV000061269 uncertain significance not specified 2017-01-18 criteria provided, single submitter clinical testing The p.Gly409Ala variant in PTPN11 has been identified in at least 2 heterozygous individuals with mild features of Noonan syndrome (Zenker 2006, Lepri 2014, LMM data) and 1 compound heterozygous individual (also carried the pathogenic p.Ser 2Gly variant in SHOC2) with a clinical diagnosis of Noonan syndrome (Ekvall 2011 ). This variant segregated with mild features of Noonan syndrome in 6 relatives from 2 families (Zenker 2006, Ekvall 2011). Please note that none of the individ uals carrying the p.Gly409Ala variant had heart defects or CNS involvement. The p.Gly409Ala variant has also been identified in 12/66642 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs201247699). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. These data suggest that this variant may cause mild features of Noonan syndrome, but more data is needed to determine this. In summary, the clinical significance of the p.Gly409A la variant is uncertain.
GeneDx RCV000037608 SCV000490756 uncertain significance not specified 2016-02-20 criteria provided, single submitter clinical testing The G409A variant in the PTPN11 gene has been reported to co-segregate with Noonan syndrome in five individuals from one family, however these individuals had mild features and did not have any cardiac findings (Zenker et al., 2007). Additionally, Lepri et al. (2014) reported G409A in one individual with suspected Noonan syndrome, but clinical and segregation information was not provided. G409A was also reported in a proband with severe Noonan syndrome who also harbored a de novo SHOC2 variant. A parent and sibling harbored only G409A and had mild features of Noonan syndrome(Ekvall et al., 2011). The G409A variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G409A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G409A as a variant of uncertain significance
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626827 SCV000747530 uncertain significance Neurofibromas 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037608 SCV000918106 uncertain significance not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1226G>C (p.Gly409Ala) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.1226G>C has been reported in the literature in heterozygosity in individuals affected with mild features of Noonan Syndrome and Related Conditions (NSRD) in two families (Zenker 2007, Ekvall 2011) and was found in a cohort of individuals with suspected Noonan Syndrome (Lepri 2014). These reports do not provide unequivocal conclusions about association of the variant with NSRD. Co-occurrences with other pathogenic variant(s) have been reported (SHOC2 c.4A>G , p.Ser2Gly), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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