Submissions for variant NM_005633.4(SOS1):c.1385T>A (p.Phe462Tyr)

gnomAD frequency: 0.00001  dbSNP: rs730881043

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159167	SCV000209112	uncertain significance	not provided	2020-03-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function
Mendelics	RCV002247418	SCV002519388	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390136	SCV002699883	uncertain significance	Cardiovascular phenotype	2022-04-03	criteria provided, single submitter	clinical testing	The p.F462Y variant (also known as c.1385T>A), located in coding exon 10 of the SOS1 gene, results from a T to A substitution at nucleotide position 1385. The phenylalanine at codon 462 is replaced by tyrosine, 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	RCV002467513	SCV002763414	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467512	SCV002763415	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654182	SCV004552499	uncertain significance	RASopathy	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 462 of the SOS1 protein (p.Phe462Tyr). This variant is present in population databases (rs730881043, gnomAD 0.003%). 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: 40674). 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. 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.