ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.775T>C (p.Ser259Pro) (rs3730271)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781806 SCV000920140 likely pathogenic Rasopathy 2018-01-29 criteria provided, single submitter clinical testing Variant summary: RAF1 c.775T>C (p.Ser259Pro) located in the conserved region 2 (CR2) domain causes an alteration of a conserved nucleotide that alters a phosphorylation site (Kobayashi_2010). Four of five in-silico tools predict a damaging effect of the variant on protein function. Functional studies, Kobayashi_2010 and Pandit_2007, indicate that Ser259 is a phosphorylation site that plays a key role in RAF1 regulation, although the variant of interest was not directly evaluated. Other variants affecting codon 259 have been reported as Pathogneic/Likely Pathogenic in ClinVar (p.Ser259Phe, Ser259Thr), further evidence of the importance of this codon. The variant was absent in 246244 control chromosomes (gnomAD). Multiple publications, Bhoj_202016 and Cronnen_2013, cite the variant in Noonan patients including one being indicated as a de novo event. A clinical diagnostic laboratory (evaluation after 2014) classified the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000215259 SCV000271260 likely pathogenic Noonan syndrome 2015-10-08 criteria provided, single submitter clinical testing The p.Ser259Pro variant in RAF1 has been previously identified as a de novo vari ant in 1 fetus with abnormal ultrasound findings, including cystic hygroma and C HD (Croonen 2013). It was absent from large population studies. In addition, two different amino acid changes at this position (p.Ser259Phe, p.Ser259Tyr) have b een identified in multiple individuals with Noonan spectrum disorders, suggestin g a change at this position may not be tolerated (Pandit 2007, Kobayashi 2009, L MM unpublished data). In vitro functional studies suggest that decreased phospho rylation of the wildtype Serine (Ser) at position 259 may impact protein functio n (Kobayashi 2009); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical signif icance, the p.Ser259Pro variant is likely pathogenic.

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