ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1457A>G (p.Asp486Gly) (rs397516815)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000434022 SCV000706413 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing
GeneDx RCV000434022 SCV000514364 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing The D486G variant has been reported previously in association with Noonan syndrome, including an apparently de novo occurrence (Pandit et al., 2007; Croonen et al., 2013; van Trier et al., 2015). D486G has also been observed to occur apparently de novo at GeneDx. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. D486G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (D486N) and in a nearby residue (T491R/I) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
Invitae RCV000555975 SCV000659054 likely pathogenic Rasopathy 2017-05-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 486 of the RAF1 protein (p.Asp486Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 23885229), including one individual where it has been shown to arise de novo (PMID: 17603483). ClinVar contains an entry for this variant (Variation ID: 40618). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been observed to arise de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037675 SCV000061337 likely pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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