ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1403C>T (p.Thr468Met) (rs121918457)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000208002 SCV000616375 pathogenic Noonan syndrome with multiple lentigines 2017-04-03 reviewed by expert panel curation 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.
GeneDx RCV000077851 SCV000057438 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The T468M missense pathogenic variant in the PTPN11 gene has been reported as de novo and in families with Noonan syndrome with multiple lentigines (previously known as LEOPARD syndrome) (Digilio et al., 2002; Santoro et al., 2014; Spatola et al., 2015). The T468M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T468M lies in the PTP domain of the encoded protein which plays an essential role in catalytic activity. Threonine 468 is conserved in several related tyrosine phosphatases, suggesting that it is integral to PTP-domain function and other residues introduced in this position are predicted to change the intrinsic structural properties of the catalytic center. In vitro functional studies indicate that the T468M variant induces 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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077851 SCV000058283 pathogenic not provided 2017-07-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000208002 SCV000061274 pathogenic Noonan syndrome with multiple lentigines 2015-01-15 criteria provided, single submitter clinical testing The p.Thr468Met variant in PTPN11 has been reported in >30 probands with clinica l features of Noonan syndrome with multiple lentigines (Digilio 2002, Keren 2004 , Tartaglia 2006, Cesarini 2009). It has also been shown to segregate with disea se in 5 affected relatives (Digilio 2002, Keren 2004, Writzl 2007). It was absen t from large population studies. In vitro functional studies and animal models i n zebrafish provide some evidence that the p.Thr468Met variant may impact protei n function (Stewart 2010). In summary, this variant meets criteria to be classif ied as pathogenic for Noonan syndrome with multiple lentigines in an autosomal d ominant manner based upon segregation studies, absence from controls, and functi onal evidence.
Invitae RCV000033533 SCV000253876 pathogenic Rasopathy 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 468 of the PTPN11 protein (p.Thr468Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs121918457, ExAC 0.02%). This is a well known PTPN11 mutation which has been reported in several individuals and families affected with LEOPARD syndrome and other Noonan spectrum disorders (PMID: 12058348, 22585553, 21910245, 22585553, 23813970, 24767283, 22555271). ClinVar contains an entry for this variant (Variation ID: 13331). A structural analysis finds that the p.Thr458 residue is located in a functionally important region of the PTPN11 protein (PMID: 16377799, 18372317). Experimental studies using mammalian cell models have shown that the p.Thr458Met protein change results in a reduction of catalytic protein function (PMID: 24935154, 16377799, 16638574, 18372317, 23457302, 20535210). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000208002 SCV000264160 pathogenic Noonan syndrome with multiple lentigines 2015-12-03 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000077851 SCV000265848 likely pathogenic not provided 2015-10-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247771 SCV000318658 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Institute of Molecular Biology and Genetics,Federal Almazov North-West Medical Research Centre RCV000055884 SCV000494585 pathogenic LEOPARD syndrome 1 2016-06-14 criteria provided, single submitter research 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.
Institute of Molecular Biology and Genetics,Federal Almazov North-West Medical Research Centre RCV000106323 SCV000494587 pathogenic Noonan syndrome 1 2016-11-16 criteria provided, single submitter research The patient was diagnosed with typical signs of Noonan syndrome and hypertrophic cardiomyopathy at the age of 2 years old.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508384 SCV000604983 pathogenic not specified 2016-11-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515406 SCV000611300 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000208002 SCV000698055 pathogenic Noonan syndrome with multiple lentigines 2017-07-10 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.1403C>T (p.Thr468Met) variant located within the "signature motif that defines the PTP family and comprises the PTP loop in PTP structures (Kontaridis_2006) that 4/4 in silico tools predict a damaging outcome, which is supported by functional studies (Kontaridis_2006). This variant was found in 1/121412 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625). Multiple publications have cited the variant in affected individuals diagnosed with LEOPARD syndrome and other Noonan spectrum disorders including mother-daughter pairs and de novo occurrences. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000077851 SCV000740649 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853462 SCV000996373 pathogenic Hypertrophic cardiomyopathy 2017-07-28 criteria provided, single submitter research 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".
Broad Institute Rare Disease Group,Broad Institute RCV000106323 SCV001164413 pathogenic Noonan syndrome 1 2018-12-03 criteria provided, single submitter research 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).
OMIM RCV000055884 SCV000034507 pathogenic LEOPARD syndrome 1 2010-06-10 no assertion criteria provided literature only
GeneReviews RCV000055884 SCV000086890 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106323 SCV000143815 not provided Noonan syndrome 1 no assertion provided not provided
Baylor Genetics RCV000033533 SCV000196651 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157014 SCV000206741 pathogenic Noonan syndrome 2009-11-03 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077851 SCV000207661 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000723326 SCV000854720 pathogenic PTPN11-related disorder 2018-07-05 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000157014 SCV001146853 pathogenic Noonan syndrome 2020-01-17 no assertion criteria provided clinical testing

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