Submissions for variant NM_002834.5(PTPN11):c.1507G>A (p.Gly503Arg)

dbSNP: rs397507545

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000077852	SCV000057451	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Not observed 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: 18678287, 28628100, 15928039, 23513489, 24803665, 25533962, 27288520, 25862627, 28135719, 16358218, 28191890, 18470943, 23756559, 22465605, 30202406, 30050098, 29907801, 32164556, 33673806, 29493581, 31785789)
Eurofins Ntd Llc (ga)	RCV000077852	SCV000058284	pathogenic	not provided	2017-11-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824749	SCV000061282	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2018-03-23	criteria provided, single submitter	clinical testing	The p.Gly503Arg (c.1507G>A) variant in PTPN11 has been reported as a somatic cha nge in at least 1 individual with a hematologic malignancy and as a germline cha nge in >10 individuals with clinical features of Noonan syndrome, including at l east 1 apparently de novo occurrence (Tartaglia 2006, Ferrero 2008, Cammarata-Sc alisi 2012, LMM data). This variant has also been reported in ClinVar (Variation ID 40559) and was absent from large population studies. In addition, the p.Gly5 03Arg variant due to a different nucleotide substitution (c.1507G>C) has also be en reported in individuals with Noonan syndrome, Noonan syndrome with juvenile m yelomonocytic leukemia (JMML), JMML, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Tartaglia 2006, Lo 2008). Three other variants involving this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as pathogenic. Computational prediction tools and conservation analysis suggest that the p.Gly5 03Arg variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner . ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3.
Invitae	RCV000033546	SCV000549991	pathogenic	RASopathy	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 503 of the PTPN11 protein (p.Gly503Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or Noonan syndrome with multiple lentigines (PMID: 15001945, 16358218, 18678287, 18758896, 22465605, 23513489). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40559). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000618529	SCV000736863	pathogenic	Cardiovascular phenotype	2022-11-21	criteria provided, single submitter	clinical testing	The p.G503R pathogenic mutation (also known as c.1507G>A), located in coding exon 13 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and c.1507G>T which leads to the same amino acid change, have been reported in a number of individuals with Noonan syndrome and related malignancies (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Lo FS et al. Int. J. Hematol., 2008 Oct;88:287-90; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Holmfeldt L et al. Nat. Genet., 2013 Mar;45:242-52; Mathur D et al. Fetal Pediatr Pathol, 2014 Aug;33:253-7). Based on internal structural analysis, this variant is predicted to be structurally destabilizing (Hof P et al. Cell. 1998 Feb;92(4):441-50; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660241	SCV000782255	pathogenic	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762886	SCV000893274	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077852	SCV001247471	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000077852	SCV001447957	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000660241	SCV001522571	pathogenic	Noonan syndrome 1	2022-08-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813261	SCV002060617	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-06-21	criteria provided, single submitter	clinical testing
3billion	RCV000660241	SCV002318911	pathogenic	Noonan syndrome 1	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040558,VCV000040559,VCV000571101). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040561, PMID:16358218). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992>=0.6, 3CNET: 0.994>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000660241	SCV002512406	pathogenic	Noonan syndrome 1	2021-07-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS1 strong, PS4 strong, PM2 moderate, PP2 supporting, PP3 supporting
MGZ Medical Genetics Center	RCV000660241	SCV002580537	pathogenic	Noonan syndrome 1	2023-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147311	SCV003835297	pathogenic	LEOPARD syndrome 1	2022-08-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147310	SCV003835451	pathogenic	Metachondromatosis	2022-08-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000660241	SCV003921809	pathogenic	Noonan syndrome 1	2021-05-07	criteria provided, single submitter	clinical testing	0103 - Both loss and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) is associated with loss of function variants, whereas Noonan syndrome (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). Variants that cause Noonan syndrome with multiple lentigines have a loss of function effect at the protein level but result in gain of function properties (PMID: 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygotes, 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, PMID: 32164556). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome in ClinVar and the literature (ClinVar, PMID: 32164556). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Eurofins-Biomnis	RCV000660241	SCV003935090	pathogenic	Noonan syndrome 1	2022-11-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000660241	SCV004175750	pathogenic	Noonan syndrome 1	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.1507G>A (p.Gly503Arg) variant in the PTPN11 gene has been observed in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (Cammarata-Scalisi, Francisco et al., 2012). It has also been observed to segregate with disease in related individuals. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic (multiple submissions). The amino acid Glycine at position 503 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT.The amino acid change p.Gly503Arg in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004532495	SCV004734343	pathogenic	PTPN11-related disorder	2023-11-28	criteria provided, single submitter	clinical testing	The PTPN11 c.1507G>A variant is predicted to result in the amino acid substitution p.Gly503Arg. This variant has been reported as a recurrent variant to be causative for Noonan syndrome and neurodevelopment disorders (see for example - Tartaglia et al. 2006. PubMed ID: 16358218; Cammarata-Scalisi et al. 2012. PubMed ID: 23513489; Geisheker et al. 2017. PubMed ID: 28628100, reported as de novo in Table S4; Leach et al. 2019. PubMed ID: 29907801, Table 2). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, an alternate nucleotide substitution (c.1507G>C) resulting in the same missense variant (p.Gly503Arg) and alternate missense variants (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) affecting this amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157015	SCV000206742	pathogenic	Noonan syndrome	2010-08-27	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000660241	SCV001133024	pathogenic	Noonan syndrome 1	2019-09-26	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000660241	SCV004167621	pathogenic	Noonan syndrome 1	2022-12-05	no assertion criteria provided	clinical testing