ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1391G>C (p.Gly464Ala) (rs121918469)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077850 SCV000281117 pathogenic not provided 2014-08-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077850 SCV000058282 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000077850 SCV000057436 pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing The G464A pathogenic variant in the PTPN11 gene has been reported in association with Noonan Syndrome with multiple lentigines (NSML and formerly called LEOPARD syndrome) and Noonan syndrome (Sarkozy et al., 2004; Ko et al., 2008; Ferrero et al., 2008; Willig et al., 2015). The G464A variant was first reported in a mother and daughter with multiple lentigines and facial dysmorphism in the absence of cardiac involvement (Sarkozy et al., 2004). This variant was subsequently reported as de novo in an infant with hypertrophic cardiomyopathy, increased neck folds, low set ears and hypotonia with a suspected diagnosis of Noonan syndrome (Willig et al., 2015). The G464A pathogenic 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. G464A results in a conservative amino acid substitution at a position that is conserved across species. G464A is located in the P-loop of the PTP domain of the SHP2 protein and functional studies have shown expression of this variant results in reduced catalytic activity (Kontaridis et al., 2006; Yu et al., 2014). Variants in nearby residues (A461T, A461S, T468P, T468M) have been reported in HGMD in association with NSML (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
GeneReviews RCV000055883 SCV000086889 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000033531 SCV000549989 pathogenic Rasopathy 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 464 of the PTPN11 protein (p.Gly464Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with LEOPARD syndrome and Noonan syndrome, arising de novo in at least one case (PMID: 15121796, 15389709, 16358218, 18678287, 19020799, 25937001). ClinVar contains an entry for this variant (Variation ID: 13343). Experimental studies have shown that this missense change alters PTPN11 protein structure and abrogates its catalytic activity (PMID: 16377799, 24935154). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824746 SCV000203928 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2014-03-04 criteria provided, single submitter clinical testing The p.Gly464Ala variant in PTPN11 has been reported in at least 2 individuals wi th clinical features of Noonan syndrome or LEOPARD syndrome (Ko 2008, Ferrero 20 08, Kitsiou-Tzeli 2006). In addition, this variant has been identified by our la boratory in 2 individuals with clinical features of a Noonan spectrum disorder. It was absent from large population studies. Furthermore, functional studies sug gest this variant has a dominant negative effect, which is an established pathog enic mechanism in LEOPARD syndrome (Kontaridis 2006, Edouard 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan or LEO PARD syndrome in an autosomal dominant manner (http://www.partners.org/personali zedmedicine/LMM).
OMIM RCV000055883 SCV000034520 pathogenic LEOPARD syndrome 1 2004-11-01 no assertion criteria provided literature only

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