ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2197A>T (p.Ile733Phe) (rs574088829)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159127 SCV000209071 pathogenic not provided 2014-08-20 criteria provided, single submitter clinical testing p.Ile733Phe (ATC>TTC): c.2197 A>T in exon 14 of the SOS1 gene (NM_005633.3).The I733F missense mutation in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007). Functional studies have demonstrated that I773F is expected to increase RAS activation and lead to RAS GTPase cycling defects (Smith et al., 2013). The variant is found in NOONAN panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587797 SCV000698624 likely pathogenic Noonan syndrome 3 2017-04-17 criteria provided, single submitter clinical testing Variant summary: The SOS1 c.2197A>T (p.Ile733Phe) variant causes a missense change involving the alteration of a conserved nucleotide. This variant is located in the Ras-like guanine nucleotide exchange factor, N-terminal (IPR000651) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). A functional study (Smith_PNAS_2013) showed that this variant increased pERK in a cell-culture model and increased RAS exchange activation by 2-3 fold. The variant of interest has not been found in a large, broad control population datasets of ExAC and gnomAD (0/121094 and 0/245906 control chrs tested, respectively). This variant was reported by multiple studies in patients with NS (Tartaglia_NatGenet_2007, Pierpont_AJMG_2010). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV001233419 SCV001406012 pathogenic Rasopathy 2019-08-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 733 of the SOS1 protein (p.Ile733Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 17143282, 20186801, 21387466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40701). This variant has been reported to affect SOS1 protein function (PMID:23487764). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.