Submissions for variant NM_002834.5(PTPN11):c.1471C>A (p.Pro491Thr)

dbSNP: rs397507539

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033535	SCV000057440	pathogenic	not provided	2021-06-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22781091, 21526175, 26582918, 22465605, 27535533)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208219	SCV000061276	pathogenic	Noonan syndrome	2013-05-21	criteria provided, single submitter	clinical testing	The Pro491Thr variant has been reported in at least 6 individuals with clinical features of Noonan syndrome (Chan 2006, Carcavilla Urqui 2006, Ezquieta 2012, LM M unpublished data). In one of these individuals, the variant was inherited fro m an affected mother (Chan 2006). At our laboratory, we have identified this var iant in 3 individuals with clinical features of Noonan syndrome and the variant was also identified in at least one affected family member in each case. We have also tested several additional individuals with clinical features of Noonan spe ctrum disorders who had other amino acid changes at this position (Pro491Leu, Pr o491Ser, Pro491His). In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM).
Blueprint Genetics	RCV000208219	SCV000264161	pathogenic	Noonan syndrome	2015-09-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660240	SCV000782253	pathogenic	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000694590	SCV000823041	pathogenic	RASopathy	2018-03-19	criteria provided, single submitter	clinical testing	Two different missense substitutions at this codon (p.Pro491Ser and p.Pro491Leu) have been determined to be pathogenic (PMID: 22465605, 22781091). This suggests that the proline residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline with threonine at codon 491 of the PTPN11 protein (p.Pro491Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 21526175, 22465605; http://www.hkjpaed.org/details.asp?id=581&show=1234). ClinVar contains an entry for this variant (Variation ID: 40549). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").
Illumina Laboratory Services, Illumina	RCV000208219	SCV001423724	pathogenic	Noonan syndrome	2020-02-28	criteria provided, single submitter	clinical testing	The PTPN11 c.1471C>A (p.Pro491Thr) variant is a missense variant that has been reported in at least one individual affected with Noonan syndrome who inherited the variant from their affected father (Ezquieta et al. 2012). Other missense changes at the Pro491 residue, Pro491Ser, Pro491Leu and Pro491His have been reported to be pathogenic and have been found in individuals with Noonan syndrome (Binder et al. 2005; Ezquieta et al. 2012; Čizmárová et al. 2016). The p.Pro491Thr variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Based on the collective evidence, de novo origin of the variant and application of the ACMG criteria, the p.Pro491Thr variant is classified as pathogenic for Noonan syndrome.
Genomic Medicine Lab, University of California San Francisco	RCV000660240	SCV001573048	likely pathogenic	Noonan syndrome 1	2019-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000694590	SCV001983563	likely pathogenic	RASopathy	2021-09-08	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.1471C>A (p.Pro491Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Other missense variants located at this codon have been reported in patients with Noonan syndrome within the HGMD database supporting the notion of critical functional relevance of this Proline residue. The variant was absent in 251480 control chromosomes. c.1471C>A has been reported in the literature in at-least one well genotyped Spanish individual affected with Noonan Syndrome (example, Ezquieta_2012) and in another individual with Noonan syndrome in whom the possibility of a cohort/patient overlap with the earlier ascertainment cannot be excluded within the context of this evaluation (Gomez-Carballa_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical patients, confirmed de-novo origin and/or a functional study is identified, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490445	SCV002813883	likely pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-02-09	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033535	SCV001956995	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000033535	SCV001966781	pathogenic	not provided		no assertion criteria provided	clinical testing