ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.524A>G (p.His175Arg) (rs397516822)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037693 SCV000061355 pathogenic Noonan syndrome 2013-05-23 criteria provided, single submitter clinical testing The His175Arg variant in the RAF1 gene has not been previously reported in the l iterature. This variant was not identified in either parent of this individual a nd therefore likely occurred de novo, assuming that non-medical explanations inc luding alternate paternity or undisclosed adoption have been ruled out. In addit ion, this variant has been found to segregate with clinical features consistent with Noonan syndrome in four individuals in one family tested by our laboratory. The His175Arg variant has not been identified in large, ethnically-distinct pop ulations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest this variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic based on it s de novo occurrence (http://pcpgm.partners.org/LMM).
Blueprint Genetics RCV000788414 SCV000927514 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing
Invitae RCV001213204 SCV001384825 uncertain significance Rasopathy 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 175 of the RAF1 protein (p.His175Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 40594). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, Klinikum rechts der Isar RCV001254110 SCV001430040 pathogenic Noonan syndrome 5 2020-05-29 no assertion criteria provided clinical testing
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000037693 SCV001438428 likely pathogenic Noonan syndrome no assertion criteria provided clinical testing

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