NM_002834.5:c.1403C>T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS3PS4PP1_StrongPM1PP2PP3PM6_Strong
This summary comes from the ClinGen Evidence Repository: The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID:24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (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). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220134/MONDO:0007893/004
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTPN11 | NM_002834.5 | c.1403C>T | p.Thr468Met | missense_variant | Exon 12 of 16 | ENST00000351677.7 | NP_002825.3 | |
| PTPN11 | NM_001330437.2 | c.1415C>T | p.Thr472Met | missense_variant | Exon 12 of 16 | NP_001317366.1 | ||
| PTPN11 | NM_001374625.1 | c.1400C>T | p.Thr467Met | missense_variant | Exon 12 of 16 | NP_001361554.1 | ||
| PTPN11 | XM_011538613.3 | c.1412C>T | p.Thr471Met | missense_variant | Exon 12 of 16 | XP_011536915.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PTPN11 | ENST00000351677.7 | c.1403C>T | p.Thr468Met | missense_variant | Exon 12 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
| PTPN11 | ENST00000635625.1 | c.1415C>T | p.Thr472Met | missense_variant | Exon 12 of 15 | 5 | ENSP00000489597.1 | |||
| PTPN11 | ENST00000635652.1 | c.416C>T | p.Thr139Met | missense_variant | Exon 4 of 5 | 3 | ENSP00000489541.1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251186Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135746
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460722Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726744
GnomAD4 genome 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:10Other:1
The PTPN11 c.1403C>T (p.Thr468Met) variant has been reported in several individuals with clinical features of a RASopathy, and is reported to segregate with disease in at least one family (Kato H et al., PMID: 20883402; Keren B et al., PMID: 15520399; Lin IS et al., PMID: 19864201; Santoro C et al., PMID: 24767283; Spatola M et al., PMID: 25884655; Writzl K et al., PMID: 17935252). This variant has been reported in the ClinVar database as a germline pathogenic variant by many submitters, including an expert panel. This variant is only observed on 1/251,186 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a location that has been defined by the ClinGen RASopathy Expert Panel to be a hotspot or functional domain (Gelb BD et al., PMID: 29493581) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTPN11 function. In support of this prediction, functional studies show altered protein activity in several different assays (Martinelli S et al., PMID: 18372317; Oishi K et al., PMID: 18849586; Yu ZH et al., PMID: 24935154). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen RASopathy Expert Panel recommendations (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. -
The observed missense variant c.1403C>T(p.Thr468Met) in the PTPN11 gene has been reported previously in individuals with Noonan syndrome (Athota JP et. Al., 2020, Yu ZH et al. 2014). The amino acid Thr at position 468 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. Experimental studies have shown that this missense change affects PTPN11 function (Yu ZH et al. 2014). This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database (multiple submissions) as Pathogenic with a status of reviewed by expert panel. The amino acid change p.Thr468Met in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates and multiple lines of computtational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on the protein structure and function. For these reasons, this variant has been classified as Pathogenic. -
A Heterozygous Missense variant c.1403C>T in Exon 12 of the PTPN11 gene that results in the amino acid substitution p.Thr468Met was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 13331]. The observed variation has previously been reported for Noonan syndrome by Athota, Jeevana Praharsha, et al., 2020. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protei n function [Stewart, Rodney A., et al., 2010]. Prenatally, the diagnosis of Noonan syndrome has been suspected following certain ultrasound findings, such as cystic hygroma, increased nuchal translucency (NT) and hydrops fetalis [Lee, K. A., et al., 2009]. For these reasons this variant has been classified as Pathogenic. -
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16638574, 18372317, 18849586, 24935154). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013331). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12058348, 15520399, 17935252, 19864201, 20883402, 24767283, 25884655). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15520399, 17935252, 20883402, 24767283). Different missense changes at the same codon (p.Thr468Glu, p.Thr468Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040547, VCV000265663). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
The heterozygous p.Thr468Met variant in PTPN11 was identified by our study in two unrelated individuals with Noonan syndrome. This variant has been identified in 0.004484% (1/22300) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918457). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rare disease sometimes diagnosed in adulthood. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The PTPN11 gene has a low rate of benign missense variation, raising the possibility that a change in this gene may not be tolerated. This variant has been reported as pathogenic in ClinVar (Variation ID: 13331). The p.Thr468Met variant in PTPN11 has been reported in 12 individuals with Noonan syndrome in the literature (PMID: 28681392, 27659786, 27238887, 12058348, 24767283). In summary, the p.Thr468Met variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PM6_Strong, PP1_Strong, PP2, PP3 (Richards 2015). -
Based 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) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 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 affects known hotspot region or cluster of pathogenic variants (ClinGen expert panel, ClinVar). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative changes, p.(Thr468Ala) and p.(Thr468Pro), have been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic by an expert panel (ClinVar) and changes at this residue are the second most common cause of Noonan syndrome (PMID: 29493581). (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 -
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The patient was diagnosed with typical signs of Noonan syndrome and hypertrophic cardiomyopathy at the age of 2 years old. -
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not provided Pathogenic:9
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Published functional studies demonstrate a damaging effect with the T468M variant inducing a weakening of the interaction between the N-SH2 and PTP domains, which leads to a mutant protein that is more readily activated (Yu et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26607044, 26377682, 27236105, 25322695, 27484170, 17697839, 26686981, 29493581, 30025578, 28152038, 24803665, 21910245, 23813970, 20493809, 21365175, 16638574, 18372317, 18849586, 20883402, 16377799, 23457302, 22555271, 20308328, 24935154, 22585553, 25884655, 12058348, 24767283, 17935252, 27666661, 26742426, 26337637, 27659786, 26952712, 27238887, 28456002, 19174044, 29346770, 29084544, 16358218, 30762279, 29445579, 19054014, 30417923, 30050098, 31560489, 31722741, 32164556, 29907801, 31370276, 33318624, 33870545, 15520399, 32627323, 33673806, 27535533, 24077912) -
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LEOPARD syndrome 1 Pathogenic:4Other:1
PS4+PS2+PS3_Moderate+PP2 -
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The patient was diagnosed with classical LEOPARD syndrome with hypertrophic cardiomyopathy. The pathogenic allele is inherited from mother who also has typical signs of LEOPARD syndrome but without hypertrophic cardiomyopathy. -
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Noonan syndrome with multiple lentigines Pathogenic:4
Variant summary: PTPN11 c.1403C>T (p.Thr468Met) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251186 control chromosomes (gnomAD). c.1403C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (e.g. Digilio_2002, Zenker_2004, Carcavilla_2013, Athota_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be catalytically defective, affecting SHP2 phosphatase activity and inducing a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to a mutant protein that is more readily activated (e.g. Kontaridis_2006, Yu_2014). Eighteen ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The p.Thr468Met variant in PTPN11 has been reported in >30 probands with clinical features of Noonan syndrome with multiple lentigines (Digilio 2002, Keren 2004, Tartaglia 2006, Cesarini 2009). It has also been shown to segregate with disease in 5 affected relatives (Digilio 2002, Keren 2004, Writzl 2007). It was absent from large population studies. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protein function (Stewart 2010). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome with multiple lentigines in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. -
The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (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). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. -
Noonan syndrome Pathogenic:3
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24935154; 18372317; 16638574; 18849586) - PS3.The c.1403C>T;p.(Thr468Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13331; PMID: PMID 25884655; PMID: 19864201; PMID: 20883402; PMID: 15520399; PMID: 17935252; PMID: 24767283; PMID: 12058348; PMID: 15520399) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase - PMID 29493581) - PM1. This variant is not present in population databases (rs121918457- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID 25884655; 19864201; PMIDs: 20883402; 15520399; 17935252; 24767283; 12058348; 15520399) - PM6_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24767283, 17935252, 15520399, 20883402) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
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PTPN11-related disorder Pathogenic:2
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The PTPN11 c.1403C>T variant is predicted to result in the amino acid substitution p.Thr468Met. This variant has been well documented as pathogenic in multiple unrelated individuals with Noonan syndrome with or without multiple lentigines (see for example - Digilio et al. 2002. PubMed ID: 12058348; Alfieri et al. 2011. PubMed ID: 21910245). At PreventionGenetics, we previously identified this variant in several other affected patients. Functional studies find this variant results in decreased protein tyrosine phosphatase activity inhibiting EGF-evoked Erk activation (Hanna et al. 2006. PubMed ID: 16638574; Kontaridis et al. 2006. PubMed ID: 16377799). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
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PTPN11 NM_002834.4 exon 12 p.Thr468Met (c.1403C>T): This variant has been reported in the literature in several individuals with Noonan syndrome with multiple lentigines and other RASopathies; it has been seen both as a de novo variant and as segregating with disease in multiple affected family members (Digilio 2002 PMID:12058348, Keren 2004 PMID:15520399, Writzl 2007 PMID:17935252, Lin 2009 PMID:19864201, Hansen 2009 PMID:19174044, Santoro 2014 PMID:24767284, Spatola 2015 PMID:25884655, Chinton 2019 PMID:31560489, Athota 2020 PMID:32164556). This variant is present in 0.009% (1/10440) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112488466-C-T?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 also present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13331). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Hanna 2006 PMID:16638574, Kontaridis 2006 PMID:16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586, Yu 2013 PMID:23457302). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -
RASopathy Pathogenic:2
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 468 of the PTPN11 protein (p.Thr468Met). This variant is present in population databases (rs121918457, gnomAD 0.004%). This missense change has been observed in individuals with LEOPARD syndrome and other Noonan spectrum disorders (PMID: 12058348, 21910245, 22555271, 22585553, 23813970, 24767283). ClinVar contains an entry for this variant (Variation ID: 13331). 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: 16377799, 16638574, 18372317, 20535210, 23457302, 24935154). For these reasons, this variant has been classified as Pathogenic. -
Variant classified using ACMG guidelines -
Hypertrophic cardiomyopathy Pathogenic:1
The PTPN11 Thr468Met variant has been reported in over 50 probands affected with LEOPARD syndrome and other Noonan spectrum disorders, including at least 4 de novo events and has been found to segregate in multiple families (see literature). We identified PTPN11 Thr468Met in a proband of Southern Eastern European descent who was diagnosed with atypical HCM. Sanger sequencing did not identify this variant in either the proband's mother or father, hence the variant has occurred de novo in our proband. The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.000008; http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster and PolyPhen2 predict this variant to be deleterious. Functional studies suggest that the variant results in reduced catalytic function (see literature). In summary, based on identification of the variant in multiple affected probands, the occurence of affected de novo individuals, functional studies displaying an affect on the protein function, segregation of the variant in affected family members, in silico tools in support of a deleterious affect and because missense variants in PTPN11 are a known mechanism of disease in Rasopathies, we classify PTPN11 Thr468Met as "pathogenic". -
Cardiovascular phenotype Pathogenic:1
The p.T468M pathogenic mutation (also known as c.1403C>T), located in coding exon 12 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1403. The threonine at codon 468 is replaced by methionine, an amino acid with similar properties. This alteration has been well described in association with LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines), and has shown segregation among several families (Digilio MC et al. Am. J. Hum. Genet., 2002 Aug;71:389-94; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Carcavilla A et al. Eur. J. Pediatr., 2011 Aug;170:1069-74; Kindel SJ et al. J. Card. Fail., 2012 May;18:396-403). One family described included individuals with hypertrophic cardiomyopathy and overlapping clinical features of neurofibromatosis and LEOPARD syndrome (Carcavilla A et al. Eur. J. Pediatr., 2011 Aug;170:1069-74). Medulloblastoma has been reported in one individual with this mutation (Rankin J et al. Am. J. Med. Genet. A, 2013 Aug;161A:2027-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, functional analyses demonstrated that the p.T468M alteration resulted in loss of normal tyrosine phosphatase activity (Hanna N et al. FEBS Lett., 2006 May;580:2477-82; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at