Submissions for variant NM_005633.4(SOS1):c.1627T>C (p.Ser543Pro)

gnomAD frequency: 0.00001  dbSNP: rs981234810

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414260	SCV000490921	uncertain significance	not specified	2016-02-23	criteria provided, single submitter	clinical testing	The S543P variant in the SOS1 gene has not been reported previously as a pathogenic nor as a benign variant, to our knowledge. The S543P 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 S543P 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. In addition, this substitution occurs at a position where only amino acids with similar properties to Serine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (S548R, T549K, L550P) 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. We interpret S543P as a variant of uncertain significance
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588660	SCV000698613	uncertain significance	not provided	2017-06-19	criteria provided, single submitter	clinical testing	Variant summary: The SOS1 c.1627T>C (p.Ser543Pro) variant located in the PH domain-like domain (via InterPro) involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome. This variant was found in 3/214708 control chromosomes (gnomAD) at a frequency of 0.000014, which does not exceed the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003). A clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Institute of Human Genetics, University Hospital Muenster	RCV004584381	SCV002054122	uncertain significance	See cases	2021-12-05	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865285	SCV002153861	uncertain significance	RASopathy	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 543 of the SOS1 protein (p.Ser543Pro). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 372578). 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.
Genome-Nilou Lab	RCV002467771	SCV002763392	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467770	SCV002763393	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481271	SCV002792017	uncertain significance	Fibromatosis, gingival, 1; Noonan syndrome 4	2021-10-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003278793	SCV004002697	uncertain significance	Cardiovascular phenotype	2025-01-30	criteria provided, single submitter	clinical testing	The p.S543P variant (also known as c.1627T>C), located in coding exon 10 of the SOS1 gene, results from a T to C substitution at nucleotide position 1627. The serine at codon 543 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000588660	SCV004702363	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	SOS1: PM1, PM2, PP3