Submissions for variant NM_005633.4(SOS1):c.1352C>G (p.Thr451Arg)

dbSNP: rs730880218

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587209	SCV000330770	uncertain significance	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Identified in a postnatal sample sent for Noonan syndrome testing in published literature; clinical information was not provided (Leach et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30050098, 29907801, 20648242, 29493581, 17143282, 21387466, 12628188)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471377	SCV000553275	uncertain significance	RASopathy	2023-07-06	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: 280820). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 29907801). This variant is present in population databases (rs730880218, gnomAD 0.01%). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 451 of the SOS1 protein (p.Thr451Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587209	SCV000698612	uncertain significance	not provided	2016-12-24	criteria provided, single submitter	clinical testing	Variant summary: The c.1352C>G (p.Thr451Arg) in SOS1 gene is a missense change that involves a mildly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant of interest is located within Pleckstrin homology (PH) domain functional domain that is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, although the functional impact of this missense change is yet to be studied. The variant is present in the large control population dataset of ExAC at a frequency 0.000008 (1/121314 chrs tested), exclusively in individuals of Latino origin (0.00008; 1/11576 chrs tested). The latter frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in SOS1 gene (0.00003). The variant is present in a control population dataset of gmomAD exclusively in individuals of Latino origin: 0.000196 (7/35710chrs), suggesting that it may be a rare ethnic-specific functional polymorphism. However, since the data set is still in beta mode, this data was not captured in pbGP. The variant has not, to our knowledge, been identified in patients with NSRD via published reports but was cited as VUS by a reputable database/diagnostic laboratory. At this time there is not sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
Genome-Nilou Lab	RCV002467710	SCV002763421	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467709	SCV002763422	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing