Submissions for variant NM_005633.4(SOS1):c.797C>A (p.Thr266Lys)

dbSNP: rs137852812

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038570	SCV000062248	pathogenic	Noonan syndrome	2012-06-26	criteria provided, single submitter	clinical testing	The Thr266Lys variant in SOS1 has been identified in the literature in several i ndividuals with clinical features of Noonan syndrome (Ko 2008, Ferrero 2008, Den ayer 2010, Pierpont 2009, Roberts 2007). This variant has been reported to have occurred de novo in at least one individual with sporadic disease (Denayer 2010) . In summary, this variant meets our criteria to be classified as pathogenic bas ed on it occurring de novo and its high frequency in individuals with features o f Noonan syndrome (http://www.pcpgm.partners.org/lmm).
GeneDx	RCV000213007	SCV000209100	pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35131284, 34184824, 23665959, 24803665, 19953625, 23885229, 17143285, 21387466, 19020799, 18678287, 19077116, 28991257, 30417923, 31560489, 32368696)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149833	SCV000553269	pathogenic	RASopathy	2022-09-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 12869). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143285, 18678287, 19020799, 19077116, 19953625, 21387466, 22420426, 23665959, 23885229). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 266 of the SOS1 protein (p.Thr266Lys).
Fulgent Genetics, Fulgent Genetics	RCV000515403	SCV000611323	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2017-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000213007	SCV002563563	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	SOS1: PS2:Very Strong, PS4, PM2, PP3
Genome-Nilou Lab	RCV000013729	SCV002763495	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
OMIM	RCV000013729	SCV000033976	pathogenic	Noonan syndrome 4	2008-11-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000149833	SCV000196677	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000038570	SCV000206736	pathogenic	Noonan syndrome	2011-12-12	no assertion criteria provided	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV003450637	SCV004190096	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing