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rs397507529

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_002834.5(PTPN11):c.844A>G(p.Ile282Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,600,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I282M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

6
7
6

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:27

Conservation

PhyloP100: 8.95
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 16 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_002834.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-112473033-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, PTPN11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
PP5
Variant 12-112473031-A-G is Pathogenic according to our data. Variant chr12-112473031-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112473031-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.844A>G p.Ile282Val missense_variant 7/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.844A>G p.Ile282Val missense_variant 7/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1448136
Hom.:
0
Cov.:
30
AF XY:
0.00000277
AC XY:
2
AN XY:
721280
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000182
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:27
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 30, 2021Published functional studies show that I282V exhibits a gain-of-function effect on the protein (Fragale et al., 2004; Martinelli et al., 2008); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24803665, 15985475, 16263833, 21407260, 14974085, 18372317, 15834506, 19077116, 12634870, 11992261, 24183200, 24037001, 22488759, 21784453, 16377799, 11704759, 30541462, 30417923, 30050098, 29907801, 31560489, 32546215, 33300679, 34006472, 33728303) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsSep 14, 2018- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 09, 2019PS3, PS4, PM1, PM2, PP2 -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 09, 2015- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 09, 2023The PTPN11 c.844A>G; p.Ile282Val variant (rs397507529) is reported in the literature in several individuals affected with noonan syndrome including multiple de novo occurrences (Binder 2005, Inoue 2020, Jongmans 2011, Pierpont 2009, Tartaglia 2001, Tartaglia 2003, Yang 2018). This variant occurs within the highly conserved phosphotyrosine phosphatase (PTP) domain and in vitro/in vivo functional analyses demonstrate a significant increase in basal level phosphatase activity consistent with the gain-of-function disease mechanisms of noonan syndrome (Fragale 2004, Martinelli 2008, Tartaglia 2006). This variant is also reported in ClinVar (Variation ID: 40525). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 282 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.525). Based on available information, this variant is considered to be pathogenic. References: Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. PMID: 15985475. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004 Mar;23(3):267-77. PMID: 14974085. Inoue T et al. Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients. Clin Epigenetics. 2020 Jun 16;12(1):86. PMID: 32546215. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260. Martinelli S et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008 Jul 1;17(13):2018-29. PMID: 18372317. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. PMID: 19077116. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID: 12717436. Yang L et al. Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel. BMC Med Genet. 2018 Dec 12;19(1):212. PMID: 30541462. -
Noonan syndrome 1 Pathogenic:7
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterDec 08, 2020- -
Pathogenic, no assertion criteria providedresearchBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College HospitalMay 31, 2019- -
Pathogenic, no assertion criteria providedresearchInstitute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan UniversityNov 16, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensOct 04, 2021- -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000040525.21, PMID: 24037001, 22488759, and 21784453, 18372317, PS1 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg78Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000158442.1, PM5). Missense changes are a common disease-causing mechanism (PP2). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityAug 07, 2020- -
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 25, 2016Variant summary: The PTPN11 c.844A>G variant affects a conserved nucleotide, resulting in an amino acid change from Ile to Val in functionally important protein tyrosine phosphatase (PTP) domain. 2/4 in-silico tools predict this variant to be damaging, and published functional studies are consistent with the variant being an activating mutation; gain of function is a known molecular mechanism in Noonan Syndrome. This variant was not found in approximately 118834 control chromosomes; however, the variant is a known recurrent pathogenic mutation causing Noonan Syndrome reported in the literature. It has been reported in sporadic as well as familial Noonan cases. Additionally, multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 20, 2023This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 282 of the PTPN11 protein (p.Ile282Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 15834506, 19077116, 21407260). ClinVar contains an entry for this variant (Variation ID: 40525). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 14974085, 15834506, 18372317). For these reasons, this variant has been classified as Pathogenic. -
Neurodevelopmental abnormality Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneOct 28, 2021- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2023The c.844A>G (p.I282V) alteration is located in coding exon 7 of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 844, causing the isoleucine (I) at amino acid position 282 to be replaced by a valine (V). This variant is unlikely to be causative of Metachondromatosis; however, it would be expected to be causative of PTPN11-related RASopathy based on mechanism of disease. Based on data from gnomAD, the G allele has an overall frequency of 0.0006571% (1/152190) total alleles studied. The highest observed frequency was 0.006548% (1/15272) of Latino/Admixed American alleles. This alteration has been reported in multiple patients in the literature with Noonan syndrome (Tartaglia, 2001; Musante, 2003; Tartaglia, 2006) and as de novo in multiple individuals with clinical features consistent with PTPN11-related RASopathy (Swarts, 2022; DECIPHER v.9.32). Another alteration at the same codon, c.846C>G (p.I282M), has been detected in individuals who have a phenotype consistent with Noonan syndrome (Atik, 2016; Kruszka, 2017; Chinton, 2019; Castellanos, 2020). This amino acid position is highly conserved in available vertebrate species. The p.I282 amino acid is located in the PTP (catalytic) domain of the SHP-2 protein. It contributes to the hydrophobic region binding the pY-phenyl ring and interacts with N-SH2 domain residues (Tartaglia, 2006). The SHP-2 protein switches between inactive and active conformations, depending on its binding to phosphotyrosyl (pY)–containing signaling partners. In the unliganded inactive conformation, the N-SH2 domain interacts extensively with the PTP domain, blocking the active site. Functional analysis demonstrated that the p.I282V alteration perturbs the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation. This in combination with an increased intrinsic catalytic activity results in a 3-fold upregulation of SHP-2 activity (Martinelli, 2008). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneJul 07, 2021- -
PTPN11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterAug 22, 2023PS3, PS4, PM2, PP2 -
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 09, 2014The p.Ile282Val variant in PTPN11 has been reported in >20 individuals with clin ical features of Noonan syndrome or LEOPARD syndrome (Tartaglia 2001, Tartaglia 2002, Mustane 2003, Binder 2005, Tartaglia 2006, Jongmans 2011, LMM unpublished data), and is absent from large population studies. In addition, functional evid ence suggests that this variant increases the activity of the PTPN11 protein, wh ich is consistent with other pathogenic variants in PTPN11 (Fragale 2004, Tartag lia 2006, Martinelli 2008). In summary, this variant meets our criteria to be cl assified as pathogenic for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM). -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoDec 10, 2021This variant has been reported in the literature in at least 7 individuals with a clinical diagnosis or suspicion of Noonan syndrome and other RASopathies, including 2 reported de novo cases, and segregating with disease in at least 1 affected family member (selected publications: Tartaglia 2001 PMID:11704759; Jongmans 2011 PMID:21407260; Bessis 2019 PMID:30417923; Lores 2020 PMID:33300679). This variant is present in 0.007% (1/15272) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12 112473031 A G?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40525). Of note, this variant occurs in a gene with a high burden of pathogenic missense variants, consistent with a gain of function mechanism (Gelb 2018 PMID:29493581). In vitro functional studies predict that this variant will impact the protein (Fragale 2004 PID:14974085; Martinelli 2008 PMID:18372317). However, these studies may not accurately represent in vivo biological function. Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 26, 2017The p.I282V pathogenic mutation (also known as c.844A>G), located in coding exon 7 of the PTPN11 gene, results from an A to G substitution at nucleotide position 844. The isoleucine at codon 282 is replaced by valine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome) (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4). In addition, an in vitro phosphatase assay showed that this alteration results in 3-fold higher phosphatase activity compared to wild type (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 01, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Benign
0.0096
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
Cadd
Uncertain
24
Dann
Uncertain
1.0
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Uncertain
-0.043
T
MutationAssessor
Benign
1.6
L;L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.88
N;N;.
REVEL
Uncertain
0.53
Sift
Pathogenic
0.0
D;D;.
Sift4G
Benign
0.18
T;T;T
Polyphen
0.60
P;B;.
Vest4
0.74
MutPred
0.90
Loss of catalytic residue at P284 (P = 0.0303);Loss of catalytic residue at P284 (P = 0.0303);Loss of catalytic residue at P284 (P = 0.0303);
MVP
0.97
MPC
0.70
ClinPred
0.93
D
GERP RS
5.7
Varity_R
0.75
gMVP
0.47

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: rs397507529; hg19: chr12-112910835; COSMIC: COSV61011840; COSMIC: COSV61011840; API