Submissions for variant NM_005633.4(SOS1):c.2237A>G (p.Asn746Ser)

dbSNP: rs975491573

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681317	SCV000808779	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing	The V524M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has not been observed in large population cohorts (Lek et al., 2016). However, the V524M variant is a conservative amino acid substitution, and in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Additional evidence is needed to clarify pathogenicity, including observation in additional individuals, segregation data, and functional evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219886	SCV001391848	uncertain significance	RASopathy	2022-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 746 of the SOS1 protein (p.Asn746Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 561864). 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 not expected to disrupt SOS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV002467992	SCV002763316	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467991	SCV002763317	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004026168	SCV005023780	uncertain significance	Cardiovascular phenotype	2024-01-22	criteria provided, single submitter	clinical testing	The p.N746S variant (also known as c.2237A>G), located in coding exon 14 of the SOS1 gene, results from an A to G substitution at nucleotide position 2237. The asparagine at codon 746 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.