ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1490G>A (p.Arg497Gln) (rs371314838)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156991 SCV000206714 uncertain significance Noonan syndrome 2013-02-19 no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761020 SCV000890935 uncertain significance Low Grade Glioma; Childhood Visual Pathway Glioma 2016-08-26 no assertion criteria provided clinical testing
GeneDx RCV000656980 SCV000209114 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing The R497Q variant in the SOS1 gene has been reported previously in an individual with Noonan syndrome (Longoni et al., 2010). However, this individual also had a de novo pathogenic variant in the RAF1 gene, which was felt to likely be causative for the Noonan syndrome phenotype. It was suggested that the R497Q variant may be contributing the cutaneous features in the family as the variant was also found in this individual’s father and grandfather, who were noted to have mild ectodermal findings (Longoni et al., 2010). The R497Q variant was reported in another publication in an individual with features of Noonan syndrome, but was inherited from an asymptomatic parent (Lepri et al., 2011). The R497Q variant is observed in 2/18,830 (0.011%) alleles from individuals of East Asian background and 16/276,456 (0.0058%) total alleles in large population cohorts (Lek et al., 2016). The R497Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The R497Q variant is located in the Pleckstrin homology domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies demonstrate that R497Q does not affect the Ras-Erk pathway but does activate Jnk signaling in the Rac1 pathway (Longoni et al., 2010). We interpret R497Q as a variant of uncertain significance.
Invitae RCV000801491 SCV000941268 uncertain significance Rasopathy 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 497 of the SOS1 protein (p.Arg497Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs371314838, ExAC 0.01%). This variant has been reported in individuals affected with suspected Noonan syndrome (PMID: 20683980, 21387466), however one of these individuals also carried a de novo variant in RAF1 (PMID: 20683980). ClinVar contains an entry for this variant (Variation ID: 45348). Experimental studies have shown that this missense change results in up-regulation of JNK phosphorylation, but not ERK phosphorylation, which is more traditionally associated with Noonan syndrome (PMID: 20683980, 25712082). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038519 SCV000062197 uncertain significance not specified 2014-10-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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