Submissions for variant NM_005633.4(SOS1):c.788T>C (p.Ile263Thr)

dbSNP: rs1310500908

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523181	SCV000621342	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing	The I263T variant in the SOS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I263T variant is not observed in large population cohorts (Lek et al., 2016). The I263T 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 that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I263T as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269235	SCV001448553	uncertain significance	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.788T>C (p.Ile263Thr) 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 was absent in 251366 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.788T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858031	SCV002315363	uncertain significance	RASopathy	2022-04-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the SOS1 protein (p.Ile263Thr). 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: 452528). 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 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	RCV002467859	SCV002763499	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467858	SCV002763500	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing