ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1658C>T (p.Thr553Met) (rs148176616)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000037622 SCV000058287 likely benign not specified 2013-03-01 criteria provided, single submitter clinical testing
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it was also identi fied in 3 parents of unrelated probands in our laboratory who were reportedly un affected (LMM unpublished data).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.
Invitae RCV000033558 SCV000262218 likely benign Rasopathy 2020-11-13 criteria provided, single submitter clinical testing
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.
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037622 SCV000698060 likely benign not specified 2021-01-14 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1658C>T (p.Thr553Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 283484 control chromosomes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome And Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is benign. 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). c.1658C>T has been reported in the literature including a fetus with clinical features of Noonan 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. 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters and one expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign (n=3) and likely benign (n=9). Based on the evidence outlined above, the variant was classified as likely benign.
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
Ambry Genetics RCV000716841 SCV000847685 likely benign History of neurodevelopmental disorder 2018-07-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852687 SCV000995396 likely benign Primary dilated cardiomyopathy; Cardiomyopathy 2018-07-13 criteria provided, single submitter clinical testing
Mendelics RCV000988917 SCV001138830 benign Metachondromatosis 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156990 SCV000206713 uncertain significance Noonan syndrome 2014-01-07 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077855 SCV000207689 likely benign not provided 2015-01-15 no assertion criteria provided clinical testing
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000156990 SCV001438422 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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