ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.794G>A (p.Arg265Gln) (rs376607329)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624213 SCV000742712 likely pathogenic Inborn genetic diseases 2017-07-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000723292 SCV000854682 pathogenic PTPN11-related disorder 2018-05-09 no assertion criteria provided 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.
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153788 SCV000203366 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing
GeneDx RCV000153788 SCV000057406 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The R265Q pathogenic variant in the PTPN11 gene has been reported previously occurring de novo in several individuals with Noonan syndrome and has been noted to present in mild or subtle forms (Chan et al., 2006; Pannone et al., 2017). The R265Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R265Q variant is a semi-conservative amino acid substitution that occurs at a position that is conserved across species. Functional studies demonstrated that R265Q enhanced ERK phosphorylation, supporting an activating role for R265Q on the MAPK signaling cascade (Pannone et al., 2017). Missense variants in nearby residues (L261F, G268C, G268S) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2009), supporting the functional importance of this region of the protein. We interpret R265Q as a pathogenic variant.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000153788 SCV000207688 uncertain significance not provided 2015-01-15 no assertion criteria provided clinical testing
Invitae RCV000477501 SCV000549988 pathogenic Rasopathy 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 265 of the PTPN11 protein (p.Arg265Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376607329, ExAC 0.006%). This variant has been reported in the literature in several individuals with short stature, developmental delay, craniofacial anomalies and/or congenital heart defects (PMID: 27353043, 28074573). In at least two affected individuals, this variant was found to be de novo. Importantly, this variant appears to be associated with a milder form of Noonan's syndrome than is typically observed for pathogenic variants in PTPN11. ClinVar contains an entry for this variant (Variation ID: 40522). Experimental studies have demonstrated that this missense change increases the activity of the PTPN11 protein in vitro (PMID: 28074573). In summary, this variant is a rare missense change that leads to increased protein activity in vitro and has been observed to be de novo in multiple individuals with PTPN11-related disorders. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037658 SCV000061320 pathogenic Noonan syndrome 2015-09-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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