Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001071738 | SCV001237058 | uncertain significance | RASopathy | 2024-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 538 of the RAF1 protein (p.Leu538Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 864526). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAF1 protein function with a positive predictive value of 95%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193133 | SCV001361774 | uncertain significance | not specified | 2019-04-22 | criteria provided, single submitter | clinical testing | Variant summary: RAF1 c.1613T>C (p.Leu538Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR001245) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251432 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow clear conclusions about variant significance. To our knowledge, no occurrence of c.1613T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV002402488 | SCV002707953 | uncertain significance | Cardiovascular phenotype | 2024-08-28 | criteria provided, single submitter | clinical testing | The p.L538S variant (also known as c.1613T>C), located in coding exon 14 of the RAF1 gene, results from a T to C substitution at nucleotide position 1613. The leucine at codon 538 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |