Submissions for variant NM_006939.4(SOS2):c.3026A>G (p.Asn1009Ser)

gnomAD frequency: 0.00001  dbSNP: rs779413196

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526934	SCV001737699	uncertain significance	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3026A>G (p.Asn1009Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250652 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3026A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (RIT1 c.268A>G, p.Met90Val), providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002439214	SCV002754313	uncertain significance	Cardiovascular phenotype	2022-03-25	criteria provided, single submitter	clinical testing	The p.N1009S variant (also known as c.3026A>G), located in coding exon 19 of the SOS2 gene, results from an A to G substitution at nucleotide position 3026. The asparagine at codon 1009 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002468259	SCV002763015	uncertain significance	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002468259	SCV003275447	uncertain significance	Noonan syndrome 9	2023-08-17	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with SOS2-related conditions. This variant is present in population databases (rs779413196, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1009 of the SOS2 protein (p.Asn1009Ser). ClinVar contains an entry for this variant (Variation ID: 1172861). 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. 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 SOS2 protein function.