ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.228G>T (p.Glu76Asp) (rs397507514)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000033478 SCV000196662 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Blueprint Genetics RCV000254683 SCV000928217 pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000037639 SCV000840427 pathogenic Noonan syndrome 2018-04-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762884 SCV000893272 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000254683 SCV000057383 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing The E76D missense variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003). The variant is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a position within the N-SH2 domain that is conserved across species, and the N-SH2 domain is a hotspot for Noonan syndrome pathogenic variants. Functional studies have shown E76D results in abnormally increased activity levels of the PTPN11 protein (Tartaglia et al., 2006). Missense variants in the same residue (E76V/G/A) and in nearby residues (F71I/L, A72P/S/G, T73I, Q79P/R) 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. Additionally, PTPN11 has a low rate of benign missense variation, and missense variants are a common mechanism of disease in this gene. In summary, we interpet E76D as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000033478 SCV000698072 pathogenic Rasopathy 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037639 SCV000061301 pathogenic Noonan syndrome 2015-07-06 criteria provided, single submitter clinical testing The p.Glu76Asp (c.228G>T) variant in PTPN11 has been identified in at least 6 in dividuals with clinical features of Noonan syndrome (Musante 2003, Tartaglia 200 6, Power 2006, Digilio 2011, LMM unpublished data). Notably, a different nucleot ide substitution at the same position (c.228G>C) resulting in the same amino aci d change has been reported in >10 individuals with clinical features of Noonan s yndrome (Tartaglia 2001, Tartaglia 2006, Edouard 2010, LMM unpublished data). Th ese variants were absent in large population studies. In addition, functional st udies have provided some evidence that this variant may impact protein function (Keilhack 2005, Bocchinfuso 2007, Edouard 2010). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based on increased frequency in affected individuals and absence from controls and functional studies.

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