Submissions for variant NM_005633.4(SOS1):c.1642A>C (p.Ser548Arg)

dbSNP: rs397517149

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000038515	SCV000616385	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038515	SCV000062193	pathogenic	Noonan syndrome	2006-10-28	criteria provided, single submitter	clinical testing	The p.Ser548Arg variant in SOS1 has been reported in >10 individuals with clinic al features of Noonan syndrome and was de novo in at least 2 of these individual s (Tartaglia 2007, Roberts 2007, Lepri 2011, LMM unpublished data). It was absen t from large population studies. In vitro functional studies provide some eviden ce that the p.Ser548Arg variant may impact protein function (Smith et al., 2013) . In summary, this variant meets our criteria to be classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000153986	SCV000203611	pathogenic	not provided	2014-01-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000153986	SCV000209115	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Reported in multiple individuals with Noonan syndrome (Lepri et al., 2011; Hakami et al., 2016; Pierpont et al., 2009; Simsek-Kiper et al., 2013); Published functional studies showed that p.(S548R) exhibited a significant increase in exchange rate of RAS (Smith et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar Variant ID# 40678; SCV000616385.3 ); This variant is associated with the following publications: (PMID: 17143282, 17143285, 24803665, 26918529, 19077116, 22420426, 28456002, 31370276, 31560489, 29493581, 20133692, 23885229, 22465605, 19020799, 23487764, 21387466)
Ambry Genetics	RCV000623399	SCV000741658	pathogenic	Inborn genetic diseases	2016-10-24	criteria provided, single submitter	clinical testing
Invitae	RCV000654915	SCV000776821	pathogenic	RASopathy	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 548 of the SOS1 protein (p.Ser548Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 17143285, 19020799, 19077116, 20186801, 21387466, 22420426, 22465605). ClinVar contains an entry for this variant (Variation ID: 40678). 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 SOS1 protein function. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692, 23487764). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763087	SCV000893613	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000153986	SCV000927567	pathogenic	not provided	2018-03-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813287	SCV002060673	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV002054544	SCV002320777	pathogenic	Noonan syndrome 4	2022-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV003450659	SCV004190098	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing