ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1814C>T (p.Ser605Phe) (rs730881004)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253554 SCV000319670 uncertain significance Cardiovascular phenotype 2015-04-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765706 SCV000897067 uncertain significance LEOPARD syndrome 2; Noonan syndrome 5; Cardiomyopathy, dilated, 1NN 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000159088 SCV000209031 uncertain significance not specified 2016-06-27 criteria provided, single submitter clinical testing The S605F variant in the RAF1 gene has been published previously as possibly associated with Noonan syndrome and inherited from a parent lacking clear clinical manifestations of Noonan syndrome (Kneitel et al., 2015). 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. S605F 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000654968 SCV000776878 uncertain significance Rasopathy 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 605 of the RAF1 protein (p.Ser605Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs730881004, ExAC 0.003%). This variant has been reported in an individual affected with a RAF1-related disease (PMID: 26467173). ClinVar contains an entry for this variant (Variation ID: 181512). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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