Submissions for variant NM_005633.4(SOS1):c.847T>C (p.Phe283Leu)

gnomAD frequency: 0.00001  dbSNP: rs1222945881

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681410	SCV000808873	uncertain significance	not provided	2018-07-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SOS1 gene. The F283L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 4/126,600 alleles (0.003%) from individuals of non-Finnish European ancestry in large population cohorts (Lek et al., 2016). The F283L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Although no nearby missense variants have been reported in the Human Gene Mutation Database, the SOS1 gene has a low rate of benign missense variation, and missense variants are a common mechanism of disease for this gene (Stenson et al., 2014).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255587	SCV001432089	uncertain significance	not specified	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.847T>C (p.Phe283Leu) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251348 control chromosomes (gnomAD). 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.847T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (PTPN11 c.181G>A, p.Asp61Asn; in an internal LCA sample), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861896	SCV002194205	uncertain significance	RASopathy	2023-08-01	criteria provided, single submitter	clinical testing	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) 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. ClinVar contains an entry for this variant (Variation ID: 561951). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 283 of the SOS1 protein (p.Phe283Leu).
Genome-Nilou Lab	RCV002467994	SCV002763490	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467993	SCV002763491	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004026170	SCV005023623	uncertain significance	Cardiovascular phenotype	2024-02-22	criteria provided, single submitter	clinical testing	The p.F283L variant (also known as c.847T>C), located in coding exon 6 of the SOS1 gene, results from a T to C substitution at nucleotide position 847. The phenylalanine at codon 283 is replaced by leucine, 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. Based on the available evidence, the clinical significance of this alteration remains unclear.