Submissions for variant NM_006939.4(SOS2):c.791C>A (p.Thr264Lys)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Human Genetics, University Hospital Magdeburg	RCV001250766	SCV001426177	pathogenic	Noonan syndrome 9	2020-07-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as pathogenic (PS1). It is absent from gnomAD (PM2). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.713 (PP3) and the variant has been cllassified as likely pathogenic in ClinVar (PP5).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269182	SCV001448466	likely pathogenic	RASopathy	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.791C>A (p.Thr264Lys) results in a non-conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain (IPR001895) of 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 251280 control chromosomes (gnomAD). c.791C>A has been reported in the literature in individuals affected with Noonan Syndrome (Cordeddu_2015, Lissewski_2020). These data indicate that the variant may be associated with disease. Variant was functionally assessed in vitro using HEK293 cells and resulted in higher levels of GTP-bound RAS and increased signaling of Ras/MAPK pathway consistent with the known molecular mechanism of disease (Cordeddu_2015, Tidyman_2016). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001250766	SCV002763116	likely pathogenic	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001250766	SCV003920500	pathogenic	Noonan syndrome 9	2022-12-29	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as de novo in at least 2 individuals with clinical suspicion or diagnoses of Noonan syndrome (Cordeddu 2015 PMID: 26173643; Lissewski 2021 PMID: 32788663); multiple laboratories in ClinVar have also reportedly identified it as de novo in affected individuals (Variation ID: 684626). This variant is not present in gnomAD. An in vitro functional study demonstrated that this variant results in both higher levels of GTP-bound Ras protein as well as increased signaling of the Ras/MAPK pathway; these findings are consistent with the gain-of-function mechanism associated with the SOS2 gene and Noonan syndrome (Cordeddu 2015 PMID: 26173643; Tidyman 2016 PMID: 27942422). Another variant at this amino acid position (p.Thr264Arg) is pathogenic, and the p.Thr264 residue has been referred to as a mutational "hotspot" (Lissewski 2021 PMID: 32788663). Additionally, the same variant at the corresponding amino acid position in the highly homologous SOS1 gene (p.Thr266Lys) is a well-established pathogenic variant, suggesting that this variant in the SOS2 gene may be similarly deleterious (Roberts 2007 PMID: 17143285; Lissewski 2021 PMID: 32788663). Finally, evolutionary conservation and computational prediction tools support that this variant likely impacts the protein. In summary, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001250766	SCV004297089	pathogenic	Noonan syndrome 9	2023-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 264 of the SOS2 protein (p.Thr264Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26173643, 32788663). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 684626). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS2 protein function. Experimental studies have shown that this missense change affects SOS2 function (PMID: 26173643). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004588303	SCV005080456	pathogenic	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased constitutive and inducible activation of ERK/MEK and RAS (PMID: 26173643); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27942422, 32788663, 35813072, 26173643)
Yale Center for Mendelian Genomics, Yale University	RCV000845124	SCV000987060	likely pathogenic	Noonan syndrome	2015-08-03	no assertion criteria provided	literature only
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000845124	SCV001426698	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing