Submissions for variant NM_005633.4(SOS1):c.323A>G (p.Glu108Gly)

dbSNP: rs886041923

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000265265	SCV000330728	likely pathogenic	not provided	2016-08-11	criteria provided, single submitter	clinical testing	The E108G variant in the SOS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E108G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E108G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glutamic Acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (E108K) and a nearby residue (P112R) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The E108G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics	RCV002321944	SCV002610333	uncertain significance	Cardiovascular phenotype	2021-11-10	criteria provided, single submitter	clinical testing	The p.E108G variant (also known as c.323A>G), located in coding exon 3 of the SOS1 gene, results from an A to G substitution at nucleotide position 323. The glutamic acid at codon 108 is replaced by glycine, an amino acid with similar properties. A different variant affecting this codon (p.E108K, c.322G>A) has been reported in association with Noonan syndrome (Tartaglia M et al. Nat Genet. 2007 Jan;39(1):75-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.