ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1658C>T (p.Thr553Met) (rs148176616)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156990 SCV000206713 uncertain significance Noonan syndrome 2014-01-07 no assertion criteria provided clinical testing
Ambry Genetics RCV000254003 SCV000317878 likely benign Cardiovascular phenotype 2016-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Ambry Genetics RCV000716841 SCV000847685 likely benign History of neurodevelopmental disorder 2016-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077855 SCV000281565 likely benign not provided 2016-01-18 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
ClinGen RASopathy Variant Curation Expert Panel RCV000033558 SCV000616417 benign Rasopathy 2017-04-03 reviewed by expert panel curation The filtering allele frequency of the c.1658C>T (p.Thr553Met) variant in the PTPN11 gene is 0.048% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (49/66556 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Computational prediction tools and conservation analysis suggest that the p.Thr553Met variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP4.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037622 SCV000058287 likely benign not specified 2013-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000755651 SCV000883050 likely benign Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000077855 SCV000057463 benign not provided 2016-06-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077855 SCV000207689 likely benign not provided 2015-01-15 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000077855 SCV000698060 likely benign not provided 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.1658C>T (p.Thr553Met) variant involves the alteration of a conserved nucleotide. The variant is located outside of some of the known domains in the protein (InterPro). 2/4 in silico tools predict benign outcome for this variant. In addition, from analysis of sequence conservation, AA substitution diverseness and experimental functional information, this variant is categorized as having 'no effect' (Kiel_2014). This variant was found in 63/122128 control chromosomes including the broad and large populations of ExAC at a frequency of 0.0005159, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic PTPN11 variant (0.0000625), suggesting this variant is likely a benign polymorphism. Particularly in an elderly control population, this variant was found at allele frequency of 0.003 (3/1000 chromosomes), strongly supporting for a benign outcome (Beaudoin_2012). The variant has been reported in a fetus with clinical features of Noonans syndrome without information of clinical follow-up (Lee_2008), one patient with neurofibromatosis type 1 who also carried an NF1 splice site variant (Sant_2015), three patients with myocardial Infarction (Beaudoin_2012), one patient with breast cancer (Maxwell_2016), one patient with glioblastoma multiforme (Sturla_2011/TCGA database) and one lymphoid neoplasm sample (COSMIC/PMID: 22675565). However, none of the published studies provide strong evidence for or against pathogenicity. In ClinVar, majority of submitters (5/8) have classified this variant as likely benign. This variant has been identified by LMM laboratory in 5 individuals with clinical features of Noonan syndrome. However, it was also identified in 3 parents of unrelated probands who were reportedly unaffected (LMM unpublished data), strongly supporting for benign outcome. Taken together, this variant is classified as Likely Benign.
Invitae RCV000033558 SCV000262218 uncertain significance Rasopathy 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 553 of the PTPN11 protein (p.Thr553Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs148176616, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a fetus with prenatal features of Noonan syndrome (PMID: 18759865); however no clinical follow-up was reported in the paper. This variant has also been observed in an individual clinically diagnosed with neurofibromatosis with tibial pseudarthrosis (PMID: 25612910). ClinVar contains an entry for this variant (Variation ID: 40570). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037622 SCV000061284 likely benign not specified 2015-03-16 criteria provided, single submitter clinical testing p.Thr553Met in exon 14 of PTPN11: This variant has been reported in the literatu re in a fetus with increased nuchal translucency, which is a prenatal feature of Noonan syndrome. However, follow-up clinical information was not provided for t his fetus (Lee 2008). This variant has been identified by our laboratory in 5 in dividuals with clinical features of Noonan syndrome. However, it was also identi fied in 3 parents of unrelated probands in our laboratory who were reportedly un affected (LMM unpublished data). In addition, this variant has been identified i n 49/66556 European chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs148176616). Threonine (Thr) at position 553 i s not conserved in mammals or evolutionarily distant species, supporting that a change at this position may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In s ummary, the p.Thr553Met variant is classified as likely benign based on its pres ence in multiple unaffected individuals and lack of conservation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000037622 SCV000740650 likely benign not specified 2017-05-15 criteria provided, single submitter clinical testing

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