ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.766A>G (p.Arg256Gly) (rs397516825)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037699 SCV000061361 likely pathogenic Noonan syndrome 2012-05-10 criteria provided, single submitter clinical testing The Arg256Gly variant in RAF1 has not been reported in the literature nor previo usly identified by our laboratory. However, a different amino acid change at thi s position (Arg256Ser) has been identified in individuals with clinical features of Noonan syndrome, suggesting that a change to this position may not be tolera ted (Pandit 2007). Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg256Gly variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. In summary, this variant is likely to be pathogenic, though segregation studies and functional analyses are required to fully establish the pathogenicity of this variant. Individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95%, Razzaq ue 2007, Pandit 2007). The presence of a heterozygous pathogenic variant in RAF1 is consistent with a diagnosis of Noonan syndrome but this information should b e reconciled with the complete clinical history of this individual.
Invitae RCV000550843 SCV000659065 pathogenic Rasopathy 2017-09-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 256 of the RAF1 protein (p.Arg256Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). Family studies have indicated that this variant was not present in the parents of an individual with hypertrophic cardiomyopathy and short stature, which suggests that it was de novo in that affected individual (Invitae). In addition, this variant has been observed in several individuals affected with hypertrophic cardiomyopathy and Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 44631). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.

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