Submissions for variant NM_002834.5(PTPN11):c.1493G>T (p.Arg498Leu)

dbSNP: rs397507542

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212896	SCV000057445	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased phosphorylation of ERK1/2 (Yu et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15121796, 19768645, 17339163, 21677813, 24891296, 24790373, 16733669, 27666661, 18241070, 17697839, 16053901, 19737548, 24935154, 24803665, 30055033, 30417923, 30050098, 29907801, 17875892, 33318624, 33776629, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824748	SCV000203964	pathogenic	Noonan syndrome with multiple lentigines; Noonan syndrome	2013-11-11	criteria provided, single submitter	clinical testing	The Arg498Leu variant in PTPN11 has been previously reported in several individu als with the clinical features of LEOPARD syndrome or Noonan syndrome (Du-Thanh 2007, Hung 2007, Limongelli 2008, Sarkozy 2004). This variant was observed to ha ve occurred de novo in another proband identified in our laboratory (LMM unpubli shed data). This variant is absent in large population studies. Another amino ac id change at this position, Arg498Trp, has also been reported in individuals wit h Noonan spectrum disorders. In summary, this variant meets our criteria to be c lassified as pathogenic (http://pcpgm.partners.org/LMM).
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	RCV000494687	SCV000494586	pathogenic	Noonan syndrome 1	2016-08-16	criteria provided, single submitter	research	The patient has typical signs of Noonan syndrome with mild mental delay and hypertrophic cardiomyopathy
Invitae	RCV000033540	SCV000659034	pathogenic	RASopathy	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 498 of the PTPN11 protein (p.Arg498Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RASopathy spectrum disorders (PMID: 15121796, 17339163, 17875892, 18241070). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 24935154). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626828	SCV000747531	pathogenic	Scoliosis; Abnormal facial shape; Cafe-au-lait spot; Specific learning disability; Intellectual disability, mild	2017-01-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000212896	SCV000920534	pathogenic	not provided	2018-11-12	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000055886	SCV001976853	pathogenic	LEOPARD syndrome 1	2021-10-05	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813260	SCV002060595	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-02-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000494687	SCV002769089	pathogenic	Noonan syndrome 1	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, especially for variants causing Noonan syndrome (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative changes (p.(Arg498Trp), p.(Arg498Gln)) have been reported many times as pathogenic and likely pathogenic, and observed in individuals with hypertrophic cardiomyopathy (HCM), Noonan syndrome or LEOPARD syndrome (VCGS, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with LEOPARD syndrome and Noonan syndrome with or without mild delay and HCM (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV000494687	SCV004242485	pathogenic	Noonan syndrome 1	2023-12-29	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM5,PS3_SUP,PM2_SUP,PP2,PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212896	SCV004563793	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	The PTPN11 c.1493G>T; p.Arg498Leu variant (rs397507542) is reported in the literature in multiple individuals affected with LEOPARD or Noonan syndrome (Kauffman 2021, Levin 2018, Sarkozy 2004). This variant is also reported in ClinVar (Variation ID: 40554) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1492C>T, p.Arg498Trp) has been reported in individuals with LEOPARD or Noonan syndrome and is considered pathogenic (Kauffman 2021, Sarkozy 2004). Functional analyses of the variant protein found increased phosphorylation of ERK1/2. (Yu 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.941). Based on available information, this variant is considered to be pathogenic. References: Kauffman H et al. Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. Pediatr Res. 2021 Aug;90(2):444-451. PMID: 33318624. Levin MD et al. Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients. Am J Med Genet A. 2018 Aug;176(8):1711-1722. PMID: 30055033. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID: 15121796. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51. PMID: 24935154.
GeneReviews	RCV000055886	SCV000086892	not provided	LEOPARD syndrome 1		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212896	SCV001956222	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212896	SCV001969369	pathogenic	not provided		no assertion criteria provided	clinical testing