ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033479 SCV000057384 pathogenic not provided 2017-07-29 criteria provided, single submitter clinical testing The E76D missense change has been reported previously in association with Noonan syndrome (Tartaglia et al., 2001 and Tartaglia et al., 2006). E76D 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. It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is conserved across species. In vitro functional studies demonstrated that the presence of the E76D variant causes increased basal catalytic activity in comparison to wild-type protein (Bocchinfuso et al., 2007). The E76 residue is within a hot spot for pathogenic variants as a different nucleotide change (c.228 G>T) resulting in the same amino acid change, missense variants in the same residue (E76G/V/A), and missense variants in nearby residues (F71V/I/L, A72P/S/G, T73I, Q79R/P) have all 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.
Integrated Genetics/Laboratory Corporation of America RCV000472904 SCV000920096 pathogenic Rasopathy 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.228G>C (p.Glu76Asp) variant involves the alteration of a conserved nucleotide located at the SH2 domain of the protein (InterPro, Keilhack _2005, Edouard_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 215446 control chromosomes (gnomAD). This variant has been reported in many individuals with NS (Tartaglia_2001, Aoki_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies showed variant with mild (2.5-3.1 fold) basal activation compared with WT (Keilhack _2005 and Niihori_2005). A variant involving the same nucleotide, c.228G>T, leading to the same codon change E76D, has been reported in affected individuals and was classified as pathogenic by our lab, suggesting the functional importance of this codon. Taken together, this variant is classified as pathogenic.
Invitae RCV000472904 SCV000549985 pathogenic Rasopathy 2017-01-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 76 of the PTPN11 protein (p.Glu76Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (rs397507514, ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 11704759, 16358218, 18678287, 19077116). Furthermore, a different variant (c.228G>T) giving rise to the same protein effect observed here (p.Glu76Asp) has also been reported in individuals with Noonan syndrome (PMID: 12634870, 16358218, 16830086, 22190897), indicating that this residue may be critical for protein function. Experimental studies have shown that this missense change results in increased phosphatase activity compared to wild type (PMID: 11704759, 15834506, 17177198). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037638 SCV000061300 pathogenic Noonan syndrome 2011-10-05 criteria provided, single submitter clinical testing The Glu76Asp variant has been reported in at least 7 individuals with clinical f eatures of Noonan syndrome (Tartaglia 2006, Tartaglia 2001). Therefore, this var iant is highly likely to be pathogenic. The presence of a heterozygous pathogeni c variant in PTPN11 is consistent with a diagnosis of Noonan syndrome but this i nformation should be reconciled with the complete clinical history of this indiv idual.

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