12-112450364-T-G
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP3PP2PM1PM6PM2PS4PS3
This summary comes from the ClinGen Evidence Repository: The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID:12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID:22711529). 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). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp 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, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234749/MONDO:0021060/004
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
Publications
- LEOPARD syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- metachondromatosisInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | c.184T>G | p.Tyr62Asp | missense_variant | Exon 3 of 16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:8
The observed missense variant c.184T>G(p.Tyr62Asp) in PTPN11 gene has been reported in heterozygous state in multiple individuals with Noonan-like/multiple giant cell syndrome and Noonan syndrome (Athota JP, et al., 2020, Chinton J, et al., 2019). Experimental studies demonstrate a profound effect on protein structure leading to re-arrangement and upregulation of its function, specifically by destabilizing the autoinhibited conformation of the SHP2 protein (Martinelli S, et al., 2012). The c.184T>G variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions).The amino acid Tyrosine at position 62 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Tyr62Asp in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013329.17, PMID: 26817465, 19352411, 32164556, 31560489, 25533962, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.9, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome 1 (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
The PTPN11 c.184T>G (p.Tyr62Asp) variant has been reported in over 20 individuals affected with Noonan syndrome and the variant reportedly occurred de novo in at least two reported individuals (Athota JP et al., PMID: 32164556; Atik T et al., 26817465; Bertola DR et al., PMID: 17020470; Chinton J et al., PMID: 31560489; Hung CS et al., PMID: 17339163; Maheshwari M et al., PMID: 12325025; Pierpont EI et al., PMID: 19077116; Tartaglia M et al., PMID: 11992261; Yoshida R et al., PMID: 15240615). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant resides within the N-SH2 domain, amino acids 112-216, of PTPN11 is defined as a critical functional domain and functional studies show c.184T>G disrupts the autoinhibitory interaction between the N-SH2 and PTP domains, indicating that this variant impacts protein function (Martinelli S et al., PMID: 22711529). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on PTPN11 function. Other variants in the same codon, p.Thr62His, p.Try62Asn, p.Tyr62Ser, have been reported as likely pathogenic (Tartaglia M et al., PMID: 16358218; ClinVar Variation IDs:3337999, 1485945, 2756656). This variant has been classified in the ClinVar database by an expert panel and at least 20 additional submitters as pathogenic. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Metachondromatosis (MIM#156250) and Noonan syndrome 1 with or without multiple lentigines (MIM#151100, 163950), respectively (PMID: 21533187, 11992261, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. Missense variants clustered between N-SH2 and PTP domains have been reported in Noonan syndrome 1 (MIM #163950; PMID: 11992261), except variants in the active site of the PTP domain, which have been reported in Noonan syndrome with multiple lentigines (PMID: 24935154). Null variants have been reported in metachondromatosis individuals (MIM #156250; PMID: 21533187). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 – Multiple alternative amino acid changes at the same position has been observed in gnomAD (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 22711529). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in Noonan syndrome 1 (MIM#163950) and classified as pathogenic by an expert panel in ClinVar (PMID: 22711529 ). (SP) 1208- Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ACMG codes: PS2, PS3, PM2, PP3, PP5
not provided Pathogenic:6
Published functional studies demonstrate a profound effect on protein structure leading to re-arrangement and upregulation of its function, specifically by destabilizing the autoinhibited conformation of the SHP2 protein (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19077116, 28607217, 25337068, 19020799, 32164556, 24033266, 16358218, 15928039, 19352411, 17020470, 12717436, 12325025, 11992261, 24803665, 25533962, 22711529, 26817465, 29555671, 29670795, 28135719, 15240615, 28191890, 28991257, 30417923, 30050098, 29907801, 31219622, 31560489, 33300679, 32901917, 32368696, 31785789)
PS4, PS3, PM6
RASopathy Pathogenic:5
Variant summary: PTPN11 c.184T>G (p.Tyr62Asp) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). c.184T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Limal_2006, Sarkozy_2003, Tartaglia_2002). These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant resulted in increased PTPN11 activity (Martinelli_2012). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Variant classified using ACMG guidelines
The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID: 12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID: 22711529). 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). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp 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, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2.
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 62 of the PTPN11 protein (p.Tyr62Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan-like/multiple giant cell syndrome and Noonan syndrome (PMID: 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13329). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
PTPN11-related disorder Pathogenic:2
The PTPN11 c.184T>G variant is predicted to result in the amino acid substitution p.Tyr62Asp. This variant has been reported in multiple individuals with Noonan syndrome with multiple cases where the variant arose de novo (see for example - Tartaglia et al. 2002. PubMed ID: 11992261; Szot et al. 2018. PubMed ID: 29555671). 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 this variant leads to elevated levels of ERK phosphorylation (Martinelli et al. 2012. PubMed ID: 22711529). Additionally, different missense variants affecting this residue (p.Tyr62Asn and p.Tyr62Cys) have been reported as pathogenic (Tartaglia et al. 2006. PubMed ID: 16358218; Jongmans et al. 2011. PubMed ID: 21407260). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
PM2, PS4, PM6, PS3, PM1, PP3, PP2
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
PTPN11 NM_0002834.4 exon 3 p.Tyr62Asp (c.184T>G): This variant has been reported in the literature in several individuals with Noonan syndrome, including multiple de novo occurrences (Tartaglia 2002 PMID:11992261, Fitzgerald 2015 PMID:25533962, Jin 2017 PMID:28991257, Kosmicki 2017 PMID:28191890, McRae 2017 PMID:28135719, Szot 2018 PMID:29555671, Chinton 2019 PMID:31560489, Leach 2019 PMID:29907801, Athota 2020 PMID:32164556). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Expert Panel (Variation ID:13329). This variant is located within the N-terminal SH2 domain, which acts as a molecular switch between the active and inactive states of SHP2 (Hof 1998 PMID: 9491886, Martinelli 2012 PMID:22711529). An in vitro functional study has shown a gain-of-function effect of this variant on the SHP2 protein product encoded by PTPN11 (Martinelli 2012 PMID:22711529). However, this study may not accurately represent in vivo biological function. In addition, evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above.
Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
The p.Tyr62Asp variant in PTPN11 has been reported in many individuals with the clinical features of Noonan syndrome as well as an individual with Noonan syndro me and juvenile myelomonocytic leukemia (JMML; Tartaglia 2002, Tartaglia 2006, M aheshwari 2002, Bertola 2006, Beneteau 2009, LMM data). This variant has been re ported to have occurred de novo in an affected individual (Maheshwari 2002). In addition, this variant has not been identified in large population studies. In s ummary, the p.Tyr62Asp variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner.
Noonan syndrome Pathogenic:1
Cardiovascular phenotype Pathogenic:1
The p.Y62D pathogenic mutation (also known as c.184T>G), located in coding exon 3 of the PTPN11 gene, results from a T to G substitution at nucleotide position 184. The tyrosine at codon 62 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with PTPN11-related RASopathy (Maheshwari M et al. Hum. Mutat., 2002 Oct;20:298-304; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Kratz CP et al. Blood, 2005 Sep;106:2183-5; Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Bertola DR et al. Genet. Test., 2006;10:186-91; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Beneteau C et al. Eur. J. Hum. Genet., 2009 Oct;17:1216-21; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). In an assay testing PTPN11 function, this variant showed functionally abnormal results (Martinelli S et al. J. Biol. Chem., 2012 Aug;287:27066-77). Other variant(s) at the same codon, p.Y62C (c.185A>G), p.Y62N (c.184T>A), have been identified in individual(s) with features consistent with PTPN11-related RASopathy (Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Patent ductus arteriosus;C0040961:Tricuspid regurgitation;C0162770:Right ventricular hypertrophy;C0344724:Atrial septal defect, ostium secundum type;C0344974:Dysplastic pulmonary valve;C2315100:Failure to thrive Pathogenic:1
This variant was identified in an Australian family of South-East Asian descent. There was no family history of congenital heart disease, and the patient was identified with a novel (with respect to ExAC) de novo variant previously reported to cause Noonan syndrome. The patient exhibited typical cardiac features of Noonan syndrome, but further clinical examination was unavailable to confirm syndromic diagnosis.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at