Submissions for variant NM_002880.4(RAF1):c.1936C>T (p.Pro646Ser)

dbSNP: rs1060503152

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459639	SCV000552084	uncertain significance	RASopathy	2017-06-24	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 411093). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 646 of the RAF1 protein (p.Pro646Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine.
GeneDx	RCV000521424	SCV000616934	uncertain significance	not provided	2017-10-16	criteria provided, single submitter	clinical testing	The P646S variant in the RAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P646S variant is not observed in large population cohorts (Lek et al., 2016). The P646S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P646S as a variant of uncertain significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000521424	SCV000924913	uncertain significance	not provided	2017-07-14	no assertion criteria provided	provider interpretation	p.Pro646Ser (P646S; c.1936C>T) in exon 17 of the RAF1 gene (NM_002880.3) Chromosome location 3:12626024 G / A We classify this as a Variant of Uncertain Significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Proline with a polar Serine. Proline at this location is highly conserved across vertebrate species. According to the Invitae laboratory report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is absent from the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient’s ancestry is Mexican.