ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1430A>G (p.Gln477Arg)

dbSNP: rs730881044
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159168 SCV000209113 pathogenic not provided 2022-07-11 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 20648242, 29493581, 17143282, 21387466, 12628188, 20683980, 24077912)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224178 SCV003920499 likely pathogenic Fibromatosis, gingival, 1; Noonan syndrome 4 2022-12-29 criteria provided, single submitter clinical testing This variant has been reported in the literature in 3 individuals with clinical suspicion or diagnoses of Noonan syndrome, including at least once as de novo (Longoni 2010 PMID: 20683980; Lepri 2011 PMID: 21387466). It has also been reported in ClinVar, with the only submitting laboratory classifying it as pathogenic (Variation ID: 181552). This variant is absent from gnomAD. This variant is located in the PH domain of the encoded protein, which is recognized as functionally important and is enriched for pathogenic variants in affected individuals (Lepri 2011 PMID: 21387466). Further, missense variation in the SOS1 gene is frequently pathogenic (Gelb 2018 PMID: 29493581). However, evolutionary conservation and computational prediction tools are unclear on the effect of this variant on the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.

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