Submissions for variant NM_002880.4(RAF1):c.784A>C (p.Asn262His)

dbSNP: rs1575573204

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067253	SCV001232303	likely pathogenic	RASopathy	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 262 of the RAF1 protein (p.Asn262His). This variant is not present in population databases (gnomAD no frequency). 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: 860864). 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%. This variant disrupts the p.Asn262 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20052757, 30732632). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192471	SCV001360611	uncertain significance	not specified	2019-03-12	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.784A>C (p.Asn262His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246246 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.784A>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 until additional information becomes available.
Ambry Genetics	RCV002411596	SCV002670055	uncertain significance	Cardiovascular phenotype	2019-08-19	criteria provided, single submitter	clinical testing	The p.N262H variant (also known as c.784A>C), located in coding exon 6 of the RAF1 gene, results from an A to C substitution at nucleotide position 784. The asparagine at codon 262 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV005001149	SCV005626566	likely pathogenic	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Identified in fetus with a cystic hygroma, however additional clinical information was not provided (PMID: 29907801); 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15520807, 17603482, 17603483, 19020799, 24957944, 29493581, 9689060, 30050098, 29907801)
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261033	SCV001438434	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing