ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp) (rs121918460)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000033466 SCV001335317 pathogenic Rasopathy 2020-02-14 reviewed by expert panel curation The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID: 12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID: 22711529). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2.
GeneDx RCV000153794 SCV000057371 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The Y62D missense variant has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002; Tartaglia et al. 2006; Bertola et al. 2006; Maheshwari et al. 2002) and Noonan syndrome with myeloproliferative disorders (Kratz et al., 2005; Tartaglia et al. 2003). This variant also has been reported in a patient with an allelic disorder, Noonan like/Multiple Giant Cell Lesion syndrome (Beneteau et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016). In vitro functional studies confirmed that the Y62D variant results in a gain-of-function for the protein (Martinelli et al., 2012). The Y62D variant lies in the N-SH2 domain of the SHP2 protein encoded by PTPN11. This domain is the first of two sites involved in switching the protein between its inactive and active conformations. Missense variants in the same residue (Y62N, Y62C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome, supporting the functional importance of this region of the protein (Tartaglia et al., 2006; Jongmans et al., 2011). In summary, we consider the variant to be pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153794 SCV000203372 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824739 SCV000204059 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2014-05-23 criteria provided, single submitter clinical testing The p.Tyr62Asp variant in PTPN11 has been reported in many individuals with the clinical features of Noonan syndrome as well as an individual with Noonan syndro me and juvenile myelomonocytic leukemia (JMML; Tartaglia 2002, Tartaglia 2006, M aheshwari 2002, Bertola 2006, Beneteau 2009, LMM data). This variant has been re ported to have occurred de novo in an affected individual (Maheshwari 2002). In addition, this variant has not been identified in large population studies. In s ummary, the p.Tyr62Asp variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000153794 SCV000265849 pathogenic not provided 2015-10-05 criteria provided, single submitter clinical testing
Invitae RCV000033466 SCV000659042 pathogenic Rasopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 62 of the PTPN11 protein (p.Tyr62Asp). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (rs121918460, ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 11992261, 15240615, 17020470, 19020799, 26817465, 16358218) as well as an individual with Noonan-like/multiple giant cell syndrome (PMID: 19352411). In at least one of these individuals, the variant occurred de novo (PMID: 12325025). ClinVar contains an entry for this variant (Variation ID: 13329). An experimental study has shown that this missense change results in an increase of PTPN11 activity in vitro (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
Embryology Laboratory,Victor Chang Cardiac Research Institute RCV000590972 SCV000680457 pathogenic Failure to thrive; Secundum atrial septal defect; Tricuspid regurgitation; Right ventricular hypertrophy; Dysplastic pulmonary valve; Patent ductus arteriosus 2017-09-08 criteria provided, single submitter research This variant was identified in an Australian family of South-East Asian descent. There was no family history of congenital heart disease, and the patient was identified with a novel (with respect to ExAC) de novo variant previously reported to cause Noonan syndrome. The patient exhibited typical cardiac features of Noonan syndrome, but further clinical examination was unavailable to confirm syndromic diagnosis.
Integrated Genetics/Laboratory Corporation of America RCV000033466 SCV000698065 pathogenic Rasopathy 2020-04-09 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.184T>G (p.Tyr62Asp) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). c.184T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Limal_2006, Sarkozy_2003, Tartaglia_2002). These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant resulted in increased PTPN11 activity (Martinelli_2012). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762882 SCV000893270 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000153794 SCV000927995 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000014257 SCV000992537 pathogenic Noonan syndrome 1 2019-01-10 criteria provided, single submitter research ACMG codes: PS2, PS3, PM2, PP3, PP5
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000014257 SCV000999301 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
OMIM RCV000014257 SCV000034505 pathogenic Noonan syndrome 1 2002-10-01 no assertion criteria provided literature only
Baylor Genetics RCV000033466 SCV000196656 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156993 SCV000206716 pathogenic Noonan syndrome 2014-01-17 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000153794 SCV000207651 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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