ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs376607329
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Total submissions: 32
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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.
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 RCV000723292 SCV004115641 pathogenic PTPN11-related disorder 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000234910 SCV004807991 pathogenic Noonan syndrome 1 2024-03-29 criteria provided, single submitter clinical testing
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

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