Submissions for variant NM_005633.4(SOS1):c.3392G>A (p.Arg1131Lys)

gnomAD frequency: 0.00004  dbSNP: rs768113420

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795979	SCV000935462	uncertain significance	RASopathy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1131 of the SOS1 protein (p.Arg1131Lys). This variant is present in population databases (rs768113420, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SOS1-related conditions (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 40728). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SOS1 function (PMID: 29074966). 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.
GeneDx	RCV001572449	SCV001797094	uncertain significance	not provided	2019-03-26	criteria provided, single submitter	clinical testing	Identified in association with Noonan syndrome; however, detailed clinical information and segregation data were not provided (Lepri et al., 2011); A the protein level, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Functional studies indicate that this variant results in increased affinity of the protein product for the plasma membrane and subsequent excessive RAS signaling (Nakamura et al., 2017); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Observed in 0.0009% (2/233698) of global alleles in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29074966, 21387466)
Ambry Genetics	RCV002453286	SCV002617210	uncertain significance	Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.R1131K variant (also known as c.3392G>A) is located in coding exon 22 of the SOS1 gene. The arginine at codon 1131 is replaced by lysine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 22. This alteration has been reported in a cohort of individuals with Noonan syndrome, cardiofaciocutaneous syndrome, or congenital heart defects; however clinical details were limited (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002467526	SCV002763216	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467525	SCV002763217	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496505	SCV002775857	uncertain significance	Fibromatosis, gingival, 1; Noonan syndrome 4	2021-10-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387735	SCV004100159	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.3392G>A (p.Arg1131Lys) is located near a canonical splice site and results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.7e-05 in 238676 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3392G>A has been reported in the literature in an individual who was either affected with Noonan Syndrome or had features suggestive of Noonan Syndrome, however clinical details and family history/segregation data were not provided (Lepri_2011). These report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. In a functional study, the variant was found to have an increased affinity for the plasma membrane compared to the wild type protein and was associated with an increase in RAS signalling (Nakamura_2017), however, these findings do not necessarily allow for strong conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 21387466, 29074966). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001572449	SCV004237627	uncertain significance	not provided	2023-04-20	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678905	SCV000805109	uncertain significance	Noonan syndrome	2016-06-07	no assertion criteria provided	clinical testing