Submissions for variant NM_002834.5(PTPN11):c.1492C>T (p.Arg498Trp)

gnomAD frequency: 0.00001  dbSNP: rs397507541

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254686	SCV000057444	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the resulting protein is catalytically impaired, has significantly reduced basal activity, and has a reduced response to stimulation with phosphotyrosol (Edwards et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 29693080, 17056636, 30417923, 30732632, 32059087, 15121796, 24891296, 23239957, 16369799, 15928039, 20301557, 27562378, 24803665, 29356064, 29988639, 21533187, 9222968, 27521173, 11704759, 12960218, 19206169, 21500339, 24935154, 17875892, 18241070, 17339163, 26918529, 31219622, 22190897, 31370276, 33318624, 34008892, 32746448, 33726816, 29493581, 27535533)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824747	SCV000204034	pathogenic	Noonan syndrome with multiple lentigines; Noonan syndrome	2016-10-06	criteria provided, single submitter	clinical testing	The p.Arg498Trp variant in PTPN11 has been identified in at least 10 individuals with clinical features of LEOPARD syndrome (LS) or Noonan syndrome with or with out myeloproliferative disorder, and segregated with clinical features in famili es (NS/MPD; Kratz 2005, Kratz 2006, Sarkozy 2004, LMM data). It has not been ide ntified in large population studies. Missense variants in PTPN11 are strongly as sociated with Noonan spectrum disorders, and another variant (p.Arg498Leu) affec ting the same amino acid residue is known pathogenic. In summary, this variant m eets criteria to be classified as pathogenic for autosomal dominant Noonan spect rum disorders.
Ambry Genetics	RCV004018715	SCV000742100	pathogenic	Cardiovascular phenotype	2023-04-11	criteria provided, single submitter	clinical testing	The p.R498W pathogenic mutation (also known as c.1492C>T), located in coding exon 13 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1492. The arginine at codon 498 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple unrelated individuals reported to have Noonan syndrome (NS) or Noonan syndrome with multiple lentigines (NSML) or features consistent with NS/NSML, including reported de novo occurrences, and has been reported to segregate with disease features in families (Sarkozy A et al. J Med Genet, 2004 May;41:e68; Kratz CP et al. Blood, 2005 Sep;106:2183-5; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14; Edwards JJ et al. Am J Med Genet A, 2014 Sep;164A:2351-5; Ramos-Geldres TT et al. Actas Dermosifiliogr, 2015 May;106:e19-22; Bademci G et al. Sci Rep, 2016 Aug;6:31622; Hakami F et al. Prenat Diagn, 2016 May;36:418-23; McDonald BS et al. Clin Exp Dermatol, 2018 Apr;43:357-359; Bulteel C et al. JAAD Case Rep, 2018 May;4:390-391; Giugliano T et al. Genes (Basel), 2019 Jul;10; Li X et al. Clin Genet, 2019 Oct;96:290-299; Bessis D et al. Br J Dermatol, 2019 Jun;180:1438-1448; Kauffman H et al. Pediatr Res, 2021 Aug;90:444-451; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033539	SCV000824558	pathogenic	RASopathy	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 498 of the PTPN11 protein (p.Arg498Trp). This variant is present in population databases (rs397507541, gnomAD 0.0009%). This missense change has been observed in individual(s) with Noonan syndrome with multiple lentigines and PTPN11-related conditions (PMID: 15121796, 22190897, 24891296, 27562378; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40553). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 24891296). This variant disrupts the p.Arg498 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15121796, 17339163, 17875892, 18241070, 24935154). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000722171	SCV000854620	pathogenic	Noonan syndrome 1	2024-01-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000254686	SCV000886027	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	The PTPN11 c.1492C>T; p.Arg498Trp variant (rs397507541) is reported in the literature in multiple individuals diagnosed with Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome 1) or Noonan syndrome (Chen 2019, Giugliano 2019, Hakami 2016, Kauffman 2021, Li 2019, Marinakis 2021, Sarkozy 2004). This variant is also reported in ClinVar (Variation ID: 40553). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another amino acid substitution at this codon (c.1493G>T; p.Arg498Leu) has been reported in individuals with Noonan syndrome with multiple lentigines or Noonan syndrome, and is considered pathogenic (Hung 2007, Limongelli 2008, Sarkozy 2004). In vitro functional analyses of the variant protein demonstrate loss of phosphatase activity, consistent with established disease mechanisms of Noonan syndrome with multiple lentigines (Gelb 2007, Rauen 2013). Computational analyses predict that this variant is deleterious (REVEL: 0.849). Based on available information, this variant is considered to be pathogenic. References: Chen H et al. Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. Orphanet J Rare Dis. 2019 Feb 7;14(1):29. PMID: 30732632. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. PMID: 24891296. Giugliano T et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8):580. PMID: 31370276. Gelb BD and Tartaglia M. Noonan Syndrome with Multiple Lentigines. 2007 Nov 30 [updated 2022 Jun 30]. GeneReviews® [Internet]. 1993–2023. PMID: 20301557. Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Hung CS et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. PMID: 17339163. 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. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Limongelli G et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet A. 2008 Mar 1;146A(5):620-8. PMID: 18241070. Marinakis NM et al. Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. Am J Med Genet A. 2021 Aug;185(8):2561-2571. PMID: 34008892. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. PMID: 23875798. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000254686	SCV001247470	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000055885	SCV001367276	pathogenic	LEOPARD syndrome 1	2019-08-27	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000722171	SCV001429421	pathogenic	Noonan syndrome 1	2018-11-13	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000722171	SCV001976693	pathogenic	Noonan syndrome 1	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
3billion	RCV000055885	SCV002058975	pathogenic	LEOPARD syndrome 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040553, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040554, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.849, 3CNET: 0.858, PP3_P). A missense variant is a common mechanism associated with LEOPARD syndrome 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813259	SCV002060584	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-06-01	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000722171	SCV002559209	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490447	SCV002787314	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000254686	SCV003819000	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000254686	SCV004226879	pathogenic	not provided	2023-01-11	criteria provided, single submitter	clinical testing	PP2, PP3, PM5, PS2, PS3_moderate, PS4
Institute of Human Genetics, Medical University Innsbruck	RCV004018715	SCV005044711	pathogenic	Cardiovascular phenotype		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000055885	SCV005049318	pathogenic	LEOPARD syndrome 1	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004558285	SCV005049470	pathogenic	Metachondromatosis	2024-02-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000722171	SCV005087128	pathogenic	Noonan syndrome 1	2023-12-21	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 - Both loss of function 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; ClinGen expert panel). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome is known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in individuals with LEOPARD syndrome or Noonan syndrome (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002490447	SCV005880060	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1		criteria provided, single submitter	clinical testing	PP2+PP3+PM6+PS4+PM1
GeneReviews	RCV000055885	SCV000086891	not provided	LEOPARD syndrome 1		no assertion provided	literature only
Baylor Genetics	RCV000033539	SCV000196653	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
PreventionGenetics, part of Exact Sciences	RCV004532493	SCV004113039	pathogenic	PTPN11-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The PTPN11 c.1492C>T variant is predicted to result in the amino acid substitution p.Arg498Trp. This variant has been reported to be causative for Noonan spectrum disorders (see for example, Sarkozy et al. 2004. PubMed ID: 15121796). Functional studies demonstrate this variant results in reduced phosphatase activity (Edwards et al. 2014. PubMed ID: 24891296). This variant is also interpreted by multiple clinical labs as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40553/). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.