Submissions for variant NM_002834.5(PTPN11):c.794G>A (p.Arg265Gln)

gnomAD frequency: 0.00003  dbSNP: rs376607329

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000037658	SCV000616412	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.794G>A p.Arg265Gln variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's:26957, 21766, 506381, 28338; ClinVar SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). The variant has been reported in the literature to segregate with clinical features of a RASopathy in at least 3 family members (PP1; APHP-Robert Debré Hospital internal data; GTR ID: 28338). The p.Arg265Gln variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR Lab ID: 26957, 21766, 506381, 28338; SCV000203366.6; SCV000061320.5; SCV000057406.11; SCV000207688.1). In vitro functional studies provide some evidence that the p.Arg265Gln variant may impact protein function (PS3; PMID 28074573). 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). The 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, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1, PS4_Moderate, PS3, PM1, PP2.
GeneDx	RCV000153788	SCV000057406	pathogenic	not provided	2021-09-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R265Q enhances ERK phosphorylation, supporting an activating role for R265Q on the MAPK signaling cascade (Pannone et al., 2017); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27353043, 29493581, 32233106, 28074573, 30602027, 31172509, 16053901, 9491886, 11992261, 34006472, 32719394)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037658	SCV000061320	pathogenic	Noonan syndrome	2015-09-29	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga)	RCV000153788	SCV000203366	pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000234910	SCV000292235	likely pathogenic	Noonan syndrome 1	2015-05-26	criteria provided, single submitter	clinical testing	Pathogenic mutations in the PTPN11 gene have been reported to cause Noonan syndrome. This de novo mutation in PTPN11 gene is likely involved in the development delay of this young patient.
Invitae	RCV000477501	SCV000549988	pathogenic	RASopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 265 of the PTPN11 protein (p.Arg265Gln). This variant is present in population databases (rs376607329, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 27353043, 28074573). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40522). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 28074573). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000624213	SCV000742712	pathogenic	Inborn genetic diseases	2017-07-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000988915	SCV001138828	pathogenic	Metachondromatosis	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253554	SCV001429331	pathogenic	LEOPARD syndrome 1	2020-02-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001536068	SCV001752765	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-07-16	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000153788	SCV001832394	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000234910	SCV001870322	pathogenic	Noonan syndrome 1	2020-05-13	criteria provided, single submitter	research	ACMG codes:PS3, PP3, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000153788	SCV002063068	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	PTPN11: PM5, PS2:Moderate, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000234910	SCV002320811	pathogenic	Noonan syndrome 1	2022-01-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000153788	SCV002501512	pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415447	SCV002676440	pathogenic	Cardiovascular phenotype	2022-07-11	criteria provided, single submitter	clinical testing	The p.R265Q pathogenic mutation (also known as c.794G>A), located in coding exon 7 of the PTPN11 gene, results from a G to A substitution at nucleotide position 794. The arginine at codon 265 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been detected in multiple individuals with Noonan syndrome, including some de novo cases (van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). Arginine 265 is located in the protein tyrosine phosphatase domain of the PTPN11 protein and forms ionic interaction with glutamate 76 in the SRC-2 homology 2 (N-SH2) domain (Darian E et al. Proteins, 2011 May;79:1573-88; Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). Based on our internal structural analysis, this mutation disrupts the very sensitive interface between these two domains, leading to impaired inhibition (Hof P et al. Cell, 1998 Feb;92:441-50; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63). A functional study also demonstrated that R265Q perturbs the autoinhibitory interaction between the two domains and enhances the function of the PTPN11 protein (Pannone L et al. Hum. Mutat., 2017 Apr;38:451-459). This amino acid position is highly conserved in available vertebrate species. 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000234910	SCV002759313	pathogenic	Noonan syndrome 1	2022-12-07	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000234910	SCV003807857	pathogenic	Noonan syndrome 1	2022-12-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2 strong, PS3 strong, PS4 moderated, PM1 moderated, PP1 supporting, PP2 supporting
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001536068	SCV003920365	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-12-09	criteria provided, single submitter	clinical testing	This variant has been reported in the literature and in ClinVar in numerous patients with features consistent with or suggestive of a RASopathy; this includes as de novo in several instances, and it has been shown to segregate with disease in many similarly affected family members (Selected publications: Pannone 2017 PMID: 28074573; Qiao 2020 PMID: 32719394; Ranza 2020 PMID: 32233106; Sentchordi-Montané 2021 PMID: 34516402; ClinVar Variation ID: 40522). It is present in the Genome Aggregation Database (Highest reported MAF: 0.006% [7/110252]; https://gnomad.broadinstitute.org/variant/12-112910785-G-A?dataset=gnomad_r2_1). This has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VCEP) (ClinVar Variation ID: 40522). Of note, this variant appears to be associated with a milder or even potentially distinct phenotype compared to what is typically seen in individuals with pathogenic variants in this gene (Gelb 2018 PMID: 29493581; Ranza 2020 PMID: 32233106; Sentchordi-Montané 2021 PMID: 34516402). Functional studies have suggested that this variant impacts the encoded protein and one or more of its signaling pathways (Pannone 2017 PMID: 28074573; Ranza 2020 PMID: 32233106). The ClinGen RASopathy VCEP concluded that this residue is functionally important and is considered a mutational hotspot; additionally, missense variation in the PTPN11 gene is a very common mechanism of disease (Gelb 2018 PMID: 29493581). Evolutionary conservation and computational prediction tools support that this variant is likely to impact the protein. In summary, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000477501	SCV004039154	pathogenic	RASopathy	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.794G>A (p.Arg265Gln) results in a conservative amino acid change located in the Tyrosine-specific protein phosphatase, PTPase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247274 control chromosomes (gnomAD). c.794G>A has been reported in the literature in individuals affected with Noonan Syndrome and in at least one individual the variant was observed to be de novo (examples: Forkstuen_2016, Pannone_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that R265Q enhances ERK phosphorylation supporting an activating role on MAPK signaling (Pannone_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27353043, 28074573). Twenty three submitters (including ClinGen RASopathy Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000988915	SCV004041316	pathogenic	Metachondromatosis	2023-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001253554	SCV004041404	pathogenic	LEOPARD syndrome 1	2023-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000234910	SCV004041457	pathogenic	Noonan syndrome 1	2023-01-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407392	SCV004115641	pathogenic	PTPN11-related condition	2023-02-22	criteria provided, single submitter	clinical testing	The PTPN11 c.794G>A variant is predicted to result in the amino acid substitution p.Arg265Gln. This variant has been reported in multiple unrelated individuals with Noonan syndrome and was shown to be a de novo event in at least two cases (Fokstuen et al. 2016. PubMed ID: 27353043; Pannone et al. 2017. PubMed ID: 28074573). It has also been reported in an individual with isolated short stature (Freire et al. 2019. PubMed ID: 30602027) and reported to segregate in multiple individuals from a single family with a Noonan-like presentation; however cardiac features were not present in all members (Ranza et al. 2020. PubMed ID: 32233106, Family A). Pathogenic variants in PTPN11 act in a gain-of-function manner by causing an upregulation of the RAS pathway. Consistent with this mechanism, functional studies demonstrated the p.Arg265Gln variant leads to elevated levels of ERK phosphorylation (Pannone et al. 2017. PubMed ID: 28074573). Additionally, multiple clinical labs have interpreted this variant as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40522/). This variant is interpreted as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000153788	SCV004562856	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	The PTPN11 c.794G>A; p.Arg265Gln variant (rs376607329) is reported in the literature in multiple individuals affected with Noonan syndrome (Chan 2006, Pannone 2017). This variant is also reported in ClinVar (Variation ID: 40522). This variant is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.814). Additionally, this codon is considered to be a hotspot by the ClinGen RASopathy expert panel (Gelb 2018). Functional analyses of the variant protein show gain of function (Pannone 2017), and structural studies show that arginine 265 is likely a critical mediator of interactions between the catalytic PTP domain and the regulatory N-terminal SH2 domain (Darian 2011, Hof 1998). Based on available information, this variant is considered to be pathogenic. References: Chan D et al. A clinical and molecular study of 51 Chinese families with Noonan syndrome. Hk J Pediatr (New Series). 2006 11:290-296. Darian E et al. Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase. Proteins. 2011 79(5):1573-88. PMID: 21365683. Gelb BD et al. ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. Genet Med. 2018 Nov;20(11):1334-1345. PMID: 29493581. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 92(4): 441-450. PMID: 9491886. Pannone L et al. Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. Hum Mutat. 2017 Apr;38(4):451-459. PMID: 28074573.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000234910	SCV000207688	pathogenic	Noonan syndrome 1	2023-05-13	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723292	SCV000854682	pathogenic	PTPN11-related disorder	2018-05-09	no assertion criteria provided	clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000234910	SCV001482390	likely pathogenic	Noonan syndrome 1	2019-05-31	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000153788	SCV001798952	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000153788	SCV001931683	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000153788	SCV001979425	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000234910	SCV002583428	pathogenic	Noonan syndrome 1	2022-04-05	no assertion criteria provided	clinical testing