rs376607329

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS2PS4_ModeratePS3PP2PP1PM1

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234739/MONDO:0018997/004

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PTPN11
ENST00000351677.7 missense

Scores

12
6
2

Clinical Significance

Pathogenic reviewed by expert panel P:38

Conservation

PhyloP100: 9.60
Variant links:
Genes affected
PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.794G>A p.Arg265Gln missense_variant 7/16 ENST00000351677.7 NP_002825.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.794G>A p.Arg265Gln missense_variant 7/161 NM_002834.5 ENSP00000340944 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151900
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000324
AC:
8
AN:
247274
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134216
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000635
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1460952
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
726832
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
151900
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74166
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:38
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:15
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenDec 07, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaMay 26, 2015Pathogenic 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. -
Pathogenic, criteria provided, single submitterclinical testingProvincial Medical Genetics Program of British Columbia, University of British ColumbiaJan 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 07, 2023- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyMay 13, 2020ACMG codes:PS3, PP3, PP5 -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensJan 16, 2024PS4, PM1, PM2, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Noonan syndrome. (PMID:32233106). -
Likely pathogenic, no assertion criteria providedresearchBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College HospitalMay 31, 2019- -
Pathogenic, criteria provided, single submitterclinical testingPittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical CenterMar 17, 2023This sequence variant is a single nucleotide substitution (G>A) at coding nucleotide position 794 of the PTPN11 gene which results in an arginine to glutamine amino acid change at residue 265 in the PTPN11 protein. This is a previously reported variant (ClinVar) which has been observed as a de novo or familial variant in multiple individuals with Noon syndrome (PMID: 25862627, 28074573). This variant is rare in the gnomAD control population dataset (8/247274 alleles or 0.003%). Multiple bioinformatic tools predict that this glutamic acid to glutamine amino acid change is likely to be damaging, and arginine is conserved at this protein position in all vertebrate species examined. Altering the Arg265 amino increases phosphatase activity in vitro (PMID: 28074573), and the Arg265 residue is part of a salt bridge with Glu76 (PMID: 21365683). This variant has been classified as Pathogenic by the ClinGen RASopathy Expert Panel (Accession: SCV000616412.3). Given the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM1, PP2, PS2, PS3, PS4 -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics Laboratory, University Hospital Schleswig-HolsteinApr 05, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 15, 2022ACMG classification criteria: PS2 strong, PS3 strong, PS4 moderated, PM1 moderated, PP1 supporting, PP2 supporting -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -
Pathogenic, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterMay 13, 2023- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based 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). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2+v3: 13 heterozygotes, 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 - The missense variant is consistently predicted to be damaging by multiple in silico tools and is highly conserved. (SP) 0600 - This variant is located in the tyrosine-protein phosphatase (PTP) domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals and has been classified as pathogenic by an expert panel (Clinvar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Ectopic expression of p.(Arg265Gln) variant in HEK293 cells promotes enhanced ERK phosphorylation by perturbing the autoinhibitory interaction between the SH2 and PTP domains (PMID: 28074573). (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 -
Pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PS3_Moderate+PS4+PS2_VeryStrong -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital BonnAug 27, 2024- -
not provided Pathogenic:10
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 16, 2021Published 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) -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023PTPN11: PM5, PS2:Moderate, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 30, 2019- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsNov 17, 2021- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 07, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 17, 2018- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundSep 19, 2023- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Metachondromatosis Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 07, 2023- -
LEOPARD syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 07, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 25, 2020- -
PTPN11-related disorder Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityMay 09, 2018- -
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 12, 2024The 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). This variant is reported in 0.0063% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and 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. -
Noonan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 29, 2015proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The 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. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoDec 09, 2022This 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. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 16, 2021- -
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 14, 2023Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This 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. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 11, 2022The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.75
.;.;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.88
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.1
M;M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.6
D;D;.
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0020
D;D;.
Sift4G
Benign
0.066
T;T;T
Polyphen
0.98
D;D;.
Vest4
0.87
MVP
0.98
MPC
1.1
ClinPred
0.77
D
GERP RS
5.7
Varity_R
0.90
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376607329; hg19: chr12-112910785; COSMIC: COSV61005224; COSMIC: COSV61005224; API