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

dbSNP: rs267607080

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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individuals with clinical features of Noonan syndrome (Hanna 2009, Lepri 2011, Tartaglia 20 07, Zenker 2007, LMM unpublished data).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	2023-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 432 of the SOS1 protein (p.Trp432Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 17586837, 19438935, 21387466, 22465605). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12873). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. 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.
Genome-Nilou Lab	RCV000013733	SCV002763436	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
OMIM	RCV000013733	SCV000033980	pathogenic	Noonan syndrome 4	2009-06-01	no assertion criteria provided	literature only
Department of Genetics, Beijing BioBiggen Technology Co., Ltd.	RCV000013733	SCV002540761	pathogenic	Noonan syndrome 4	2022-06-29	no assertion criteria provided	research
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV000013733	SCV003844084	pathogenic	Noonan syndrome 4	2021-09-30	no assertion criteria provided	research