ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.768G>T (p.Arg256Ser) (rs397516826)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000523940 SCV000616377 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.768G>T (p.Arg256Ser) variant in RAF1 has been reported in the literature in 1 individual with clinical features of Noonan syndrome and one individual with clinical features of Noonan syndrome with multiple lentigines. This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg256Ser variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PS3; 20679480). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037701 SCV000061363 pathogenic Noonan syndrome 2007-09-19 criteria provided, single submitter clinical testing
GeneDx RCV000159072 SCV000209014 pathogenic not provided 2019-03-19 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on protein localization and activity (Molzan et al., 2010); Identified in patients with Noonan syndrome and/or hypertrophic cardiomyopathy referred for genetic testing at GeneDx and in published literature (Pandit et al., 2007); Reported in ClinVar as pathogenic by another clinical laboratory and the ClinGen RASopathy Variant Curation Expert Panel (ClinVar Variant ID# 40599; SCV000616377.3, SCV000061363.5; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Located in the CR2 critical functional domain; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

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