ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.925G>T (p.Asp309Tyr) (rs397517180)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038575 SCV000062253 pathogenic Noonan syndrome 2017-03-20 criteria provided, single submitter clinical testing The Asp309Tyr variant in SOS1 has been identified in at least 5 individuals with the clinical features of Noonan syndrome, occurred de novo in one of these indi viduals, and segregated with phenotypic features in 2 family members of one fami ly (Narumi 2008, Roberts 2007, Zenker 2007, LMM data). This variant has been ide ntified in large population studies. In addition, functional studies showed that this variant caused an increased EGF-evoked ERK activation, which is similar to PTPN11 disease-causing variants (Roberts 2007). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal domi nant manner based upon de novo occurrence, segregation studies, extremely low al lele frequency in the general population, and supporting functional evidence.
GeneDx RCV000255002 SCV000322037 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The D309Y variant has been published previously in association with Noonan syndrome, including an instance of de novo inheritance (Roberts et al., 2007; Zenker et al., 2007; Ezquieta et al., 2012). The 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. D309Y 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. In vitro studies have shown D309Y results in increased activation of ERK and RAS (Roberts et al., 2007). Additionally, the SOS1 gene has a low rate of benign missense variation and missense variants are a common mechanism of disease in this gene. Therefore, this variant is pathogenic.

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