Submissions for variant NM_005633.4(SOS1):c.571G>A (p.Glu191Lys)

gnomAD frequency: 0.00001  dbSNP: rs886041241

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000293469	SCV000329528	uncertain significance	not provided	2018-12-14	criteria provided, single submitter	clinical testing	The E191K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E191K variant has been observed at GeneDx in a patient who also harbored a variant of uncertain significance in the RAF1 gene, and had a parent who harbored both variants (clinical information not provided). The E191K variant was not observed in approximately 6,500 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 E191K 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. While this substitution occurs at a position that is conserved across species, it is not located within a variant hot spot" or known functional domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant."
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761106	SCV000891021	uncertain significance	Noonan syndrome	2020-10-07	criteria provided, single submitter	clinical testing	The c.571G>A missense variant has a frequency of 0.000006984 (1 of 143,180 alleles) with a maximum allele frequency of 0.00002380 (1 of 42,014) in the African subpopulation. This does not been criteria for PM2 based on ClinGen's RASopathy Expert Panel consensus methods for variant interpretation (PMID: 29493581). The p.Glu191Lys variant has been identified somatically in a patient with JMML (PMID: 29437595). The variant has also been found to segregate in a pedigree with aggressive, early-onset dilated cardiomyopathy alongside an A-band TTN truncating variant, and individuals without the SOS1 variant demonstrated reduced disease severity, thus suggesting this variant's potential involvement as a genetic risk factor for dilated cardiomyopathy in this family (PMID: 32603605). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). In ERK activation studies, the p.Glu191Lys variant increased phosphorylated ERK expression relative to wild-type levels, paralleling known disease-relevant SOS1 signaling profiles (PS3; PMID: 32603605). In summary, the clinical significance of SOS1 c.571G>A (p.Glu191Lys) is uncertain based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): PS3, PP3.
Invitae	RCV001069595	SCV001234773	uncertain significance	RASopathy	2023-06-03	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 40656). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32603605). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the SOS1 protein (p.Glu191Lys).
Mendelics	RCV002247417	SCV002519389	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467504	SCV002763522	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467503	SCV002763523	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV002467504	SCV004045852	likely pathogenic	Noonan syndrome 4	2023-12-29	criteria provided, single submitter	clinical testing	This variant was identified in a patient with visual deficits and sysmorphic stigmata in line with the diagnosis of Noonan syndrome. The variant was present at low-level mosaicism (VAF 2%) in the blood DNA of the mother. Applying PS2, PM2 and PP5 the variant meets our criteria to be classified as likely pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001543363	SCV001761921	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000293469	SCV001808850	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000293469	SCV001955585	uncertain significance	not provided		no assertion criteria provided	clinical testing