ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.680+6T>C (rs371846795)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000037697 SCV000729708 likely benign not specified 2017-10-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000375889 SCV000440629 uncertain significance Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000279157 SCV000440630 uncertain significance Noonan syndrome with multiple lentigines 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000688655 SCV000816277 uncertain significance Rasopathy 2018-09-17 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the RAF1 gene. It does not directly change the encoded amino acid sequence of the RAF1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs371846795, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 44630). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037697 SCV000061359 likely benign not specified 2015-04-01 criteria provided, single submitter clinical testing c.680+6T>C in intron 6 of RAF1: This variant is not expected to have clinical si gnificance because a T>C change at this position does not diverge from the splic e consensus sequence and is therefore unlikely to impact splicing. In addition, splicing variants in RAF1 have not been proven to be pathogenic in individuals w ith Noonan spectrum disorders. This variant has been identified in 12/65314 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins; dbSNP rs371846795).

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