ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1294T>C (p.Trp432Arg) (rs267607080)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211853 SCV000062190 pathogenic Noonan syndrome 2013-06-18 criteria provided, single submitter clinical testing The Trp432Arg variant has been reported in the literature in several individuals with clinical features of Noonan syndrome (Hanna 2009, Lepri 2011, Tartaglia 20 07, Zenker 2007, LMM unpublished data). This variant showed segregation in one f amily with clinical features of Noonan syndrome and multiple giant cell lesions consistent with pathogenicity (2 meioses; Hanna 2009). This variant is highly li kely to be pathogenic.
GeneDx RCV000159161 SCV000209106 pathogenic not provided 2014-06-30 criteria provided, single submitter clinical testing The W432R missense mutation in the SOS1 gene has been reported in association with Noonan syndrome (Tartaglia et al., 2007). W432R is a non-conservative amino acid substitution that occurs within the highly conserved pleckstrin homology (PH) domain. Furthermore, the W432R 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. The variant is found in NOONAN panel(s).
Invitae RCV000818949 SCV000959588 pathogenic Rasopathy 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 432 of the SOS1 protein (p.Trp432Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with Noonan syndrome; in at least one family, it segregates with disease (PMID: 17143282, 21387466, 22465605, 17586837, 19438935). ClinVar contains an entry for this variant (Variation ID: 12873). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000818949 SCV001448596 pathogenic Rasopathy 2020-11-09 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1294T>C (p.Trp432Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251056 control chromosomes. c.1294T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions, including some de novo cases (Tartaglia_2007, Zenker_2007, Hanna_2009, Ezquieta_2012, Jin_2017). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000013733 SCV000033980 pathogenic Noonan syndrome 4 2009-06-01 no assertion criteria provided literature only

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