Submissions for variant NM_002880.4(RAF1):c.884G>C (p.Ser295Thr)

gnomAD frequency: 0.00001  dbSNP: rs191560404

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239743	SCV001412639	uncertain significance	RASopathy	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 295 of the RAF1 protein (p.Ser295Thr). This variant is present in population databases (rs191560404, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of RAF1-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 965322). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAF1 protein function with a negative 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.
New York Genome Center	RCV001239743	SCV002097877	uncertain significance	RASopathy	2021-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526094	SCV005040441	uncertain significance	not specified	2024-03-04	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.884G>C (p.Ser295Thr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 253584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.884G>C has been reported in the literature in individuals affected with features of Noonan Syndrome And Related Conditions (Leach_2019). These reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 965322). Based on the evidence outlined above, the variant was classified as uncertain significance.