ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.767A>G (p.Gln256Arg) (rs397507523)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157681 SCV000057402 likely pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The Q256R variant has been previously published in association with Noonan syndrome (Musante et al., 2003; Lepri et al., 2014), and has been observed at GeneDx apparently de novo. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Q256R is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same codon (Q256K) and in nearby residues (E258D, C259S, L261F/H) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824743 SCV000200012 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2014-12-29 criteria provided, single submitter clinical testing The p.Gln256Arg variant in PTPN11 has been reported in 8 individuals with clinic al features Noonan syndrome or LEOPARD syndrome (Musante 2003, Tartaglia 2006, L epri 2014, LMM unpublished data) but has not been identified in large population studies (ExAC,; dbSNP rs397507523). The glutamin e (Gln) at position 256 is highly conserved in mammals and across evolutionarily distant species, and disease-causing variants in PTPN11 are typically missense. In summary, the p.Gln256Arg variant meets our criteria to be classified as path ogenic for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner based upon recurrence in multiple affected individuals, extremely low frequency in the general population, high evolutionary conservation, and consistent varian t type.
Invitae RCV000033497 SCV000261696 pathogenic Rasopathy 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 256 of the PTPN11 protein (p.Gln256Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of Noonan syndrome in several families (Invitae) and has also been reported in several unrelated affected individuals (PMID: 12634870, 24451042, 16358218). ClinVar contains an entry for this variant (Variation ID: 40518). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). A study using computer modeling techniques indicates this p.Gln256Arg missense may facilitate the activation of PTPN11 (PMID: 22681964), but this prediction has not been confirmed by published functional studies. This variant disrupts the p.Gln256 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been observed in individuals with PTPN11-related conditions (PMID:15985475), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506790 SCV000604984 pathogenic not specified 2017-04-20 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000585640 SCV000693470 pathogenic Noonan syndrome 1 2017-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000033497 SCV001361725 pathogenic Rasopathy 2019-10-22 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.767A>G (p.Gln256Arg) results in a conservative amino acid change located in the PTP type protein phosphatase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249002 control chromosomes (gnomAD and publications). c.767A>G has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Musante_2003, Tartaglia_2006, Ezquieta_2012, Lepri_2014). These data indicate that the variant is likely to be associated with disease. Five ClinVar submissions (evaluation after 2014) cite the variant three times as pathogenic and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157681 SCV000207656 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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