Submissions for variant NM_006939.4(SOS2):c.674G>A (p.Arg225Gln)

gnomAD frequency: 0.00006  dbSNP: rs780580623

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV004732474	SCV005367848	uncertain significance	RASopathy	2024-09-17	reviewed by expert panel	curation	The c.674G>A (NM_006939.4(SOS2):c.674G>A (p.Arg225Gln)) variant in RIT1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 225. No ACMG/AMP evidence codes are met. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy (Version 2.1; 09/17/2024).
GeneDx	RCV000412844	SCV000491686	uncertain significance	not specified	2016-11-10	criteria provided, single submitter	clinical testing	The R225Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R225Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693191	SCV000821050	likely benign	Noonan syndrome 9	2024-12-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365451	SCV002663611	uncertain significance	Cardiovascular phenotype	2021-08-04	criteria provided, single submitter	clinical testing	The p.R225Q variant (also known as c.674G>A), located in coding exon 5 of the SOS2 gene, results from a G to A substitution at nucleotide position 674. The arginine at codon 225 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000693191	SCV002763120	uncertain significance	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000693191	SCV003822094	uncertain significance	Noonan syndrome 9	2019-08-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003884517	SCV004700910	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SOS2: BP4