ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.253T>C (p.Trp85Arg) (rs730881054)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545153 SCV000659139 likely pathogenic Rasopathy 2018-01-08 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 85 of the SOS1 protein (p.Trp85Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Noonan syndrome in a single family (Invitae). Experimental studies have shown that the p.Trp85 residue is an important component of the inhibitory domain and that another alteration at this residue (p.Trp85Ala) destabilizes this domain, leading to partial activation (PMID: 20133692). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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