Submissions for variant NM_002880.4(RAF1):c.778A>C (p.Thr260Pro)

dbSNP: rs1085307553

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489188	SCV000576709	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36554045, 24957944, 9689060, 15520807, 17603483, 29493581, 19020799, 31040167, 30359267)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856893	SCV002237776	pathogenic	RASopathy	2022-03-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr260 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 426303). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 30359267). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 260 of the RAF1 protein (p.Thr260Pro).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001856893	SCV004121880	pathogenic	RASopathy	2023-10-19	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.778A>C (p.Thr260Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.778A>C has been reported in the literature as a de-novo variant in at-least two individuals affected with features of prenatal Rasopathy/Noonan Syndrome/multiple congenital anamolies (example, Leung_2018, Stuurman_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31573083, 30359267, 31040167). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.