Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000151718 | SCV000200048 | uncertain significance | not specified | 2010-09-02 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Gly107Gly varia nt has not been previously reported in the literature or been identified in our laboratory. This variant does not result in an amino acid change, but it does al ter the first base of exon 4 which could have an effect on splicing. Splicing va riants have not been reported as part of the mutation spectrum for RAF1, which a re typically gain-of-function. |
| Gene |
RCV001538817 | SCV001756520 | likely benign | not provided | 2018-07-30 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000151718 | SCV001983564 | likely benign | not specified | 2021-09-08 | criteria provided, single submitter | clinical testing | Variant summary: RAF1 c.321T>C (p.Gly107Gly) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.321T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (SOS1 c.1656G>C, p.Arg552Ser; Internal testing), providing supporting evidence for a benign role. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. |
| Ambry Genetics | RCV002321625 | SCV002609954 | likely benign | Cardiovascular phenotype | 2021-08-02 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Labcorp Genetics |
RCV002516050 | SCV003448797 | uncertain significance | RASopathy | 2024-12-24 | criteria provided, single submitter | clinical testing | This sequence change affects codon 107 of the RAF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RAF1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201937982, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 165010). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. |