ClinVar Miner

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

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Total submissions: 2
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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).
Integrated Genetics/Laboratory Corporation of America 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.

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