ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.1127C>G (p.Thr376Ser) (rs869320687)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224178 SCV000280618 pathogenic not provided 2016-04-27 criteria provided, single submitter clinical testing
Invitae RCV000191030 SCV001408353 pathogenic Noonan syndrome 9 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 376 of the SOS2 protein (p.Thr376Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This missense variant has been observed to segregate with Noonan syndrome in families (PMID:25795793, 26173643). ClinVar contains an entry for this variant (Variation ID: 209091). This variant has been reported to affect SOS2 protein function (PMID:26173643). For these reasons, this variant has been classified as Pathogenic.
Department of Human Genetics, University Hospital Magdeburg RCV000191030 SCV001426182 pathogenic Noonan syndrome 9 2020-07-02 criteria provided, single submitter clinical testing This variant has been proven to affect protein function using functional studies (PS3). It is absent from gnomAD (PM2). A variant at the analogous position in SOS1 (c.1132A>G) has been described as pathogenic (PM5). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6) and it has been classified as pathogenic in ClinVar (PP5).
GeneDx RCV000224178 SCV001766299 pathogenic not provided 2021-06-07 criteria provided, single submitter clinical testing Published functional studies demonstrate increased RAS activation, supporting a gain of function (Cordeddu et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31573083, 29750912, 26446362, 27942422, 26173643, 25795793, 30707178)
OMIM RCV000191030 SCV000246010 pathogenic Noonan syndrome 9 2015-06-01 no assertion criteria provided literature only
Yale Center for Mendelian Genomics,Yale University RCV000845122 SCV000987058 likely pathogenic Noonan syndrome 2015-08-03 no assertion criteria provided literature only

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