ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1532C>G (p.Thr511Arg) (rs80338799)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680803 SCV000808247 likely pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The T491R variant has been published previously in association with Noonan syndrome (Pandit et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016). T491R is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same residue (T491I) and in nearby residues (D486N/G, L489F) have been reported by the Human Gene Mutation Database and/or GeneDx in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001229313 SCV001401755 uncertain significance Rasopathy 2019-09-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 491 of the RAF1 protein (p.Thr491Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Noonan syndrome (PMID: 17603483). ClinVar contains an entry for this variant (Variation ID: 13959). This variant has been reported to affect RAF1 protein function (PMID: 22826437). This variant disrupts the p.Thr491 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, 27753652, 22826437). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
OMIM RCV000014988 SCV000035244 pathogenic Noonan syndrome 5 2007-08-01 no assertion criteria provided literature only

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