Submissions for variant NM_002880.4(RAF1):c.835G>A (p.Asp279Asn)

gnomAD frequency: 0.00001  dbSNP: rs368796800

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000463867	SCV001192868	uncertain significance	RASopathy	2019-09-24	reviewed by expert panel	curation	The c.835G>A (p.Asp279Asn) variant in RAF1 has been identified in 0.01786% (lower bound of the 95% CI of 7/18394) of East Asian chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. It was also seen in 13 individuals clinically unaffected with a RASopathy (BS2; GeneDx internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS2.
GeneDx	RCV001704143	SCV000209023	likely benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463867	SCV000552096	uncertain significance	RASopathy	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 279 of the RAF1 protein (p.Asp279Asn). This variant is present in population databases (rs368796800, gnomAD 0.03%). 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: 181510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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, LabCorp	RCV000159080	SCV000698130	likely benign	not specified	2024-10-01	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.835G>A (p.Asp279Asn) alters a conserved nucleotide located at the exon-intron boundary of the RAF1 gene resulting 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. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts this variant to be benign. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251426 control chromosomes (gnomAD). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.835G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 181510). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002433709	SCV002678572	uncertain significance	Cardiovascular phenotype	2021-10-22	criteria provided, single submitter	clinical testing	The p.D279N variant (also known as c.835G>A), located in coding exon 7 of the RAF1 gene, results from a G to A substitution at nucleotide position 835. This variant impacts the first base pair of coding exon 7. The aspartic acid at codon 279 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.