ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.788T>A (p.Val263Asp) (rs397516830)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763093 SCV000893629 pathogenic LEOPARD syndrome 2; Noonan syndrome 5; Cardiomyopathy, dilated, 1NN 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000680804 SCV000808248 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The V263D variant in the RAF1 gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Schulz et al., 2012). The V263D variant is not observed in large population cohorts (Lek et al., 2016). The V263D variant 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (V263A) and nearby residues (S259T/P/F, T260I/R, P261S/A/T/L/R/H, N262I/K) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V263D as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000586507 SCV000698128 likely pathogenic Noonan syndrome 3 2016-02-15 criteria provided, single submitter clinical testing Variant summary: RAF1 c.788T>A affects a conserved nucleotide, resulting in amino acid change from Val to Asp. 4/4 in-silico tools used predict this variant to be damaging. This variant was not found in approximately 121404 control chromosomes from the broad and large populations of ExAC. This variant was found as a de novo mutation in a patient with hypoplastic left heart syndrome associated with Noonan Syndrome (Schulz_2012). Additionally, another missense mutation at the same residue p.V263G has been classified as pathogenic/likely pathogenic by three labs in ClinVar. Furthermore, there are multiple variants in this region (such as p.S259F/P/T, p.T260R/I, p.P261A/R/H/S/T, p.N262I/K, etc.), reported in patients with NS, suggesting that the region is mutational hot-spot. At least one reputable database lists the variant as disease-causing. Taken together, this variant has currently been classified as a Probable Disease Variant/Likely Pathogenic.

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