ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.601A>G (p.Ile201Val) (rs757700986)

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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 RCV000765707 SCV000897068 uncertain significance LEOPARD syndrome 2; Noonan syndrome 5; Cardiomyopathy, dilated, 1NN 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000498661 SCV000590707 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing The I201V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I201V variant is observed in 2/11004 (0.018%) alleles from individuals of Latino background, in the ExAC dataset (Lek et al., 2016). The I201V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. However, RAF1 and the other genes of the Ras/MAPK signalling pathway are very intolerant of sequence changes and there are few known benign amino acid substitutions. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000558397 SCV000659060 uncertain significance Rasopathy 2017-05-23 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 201 of the RAF1 protein (p.Ile201Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs757700986, ExAC 0.02%) but has not been reported in the literature in individuals with a RAF1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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