ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.779C>A (p.Thr260Lys) (rs869025501)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000792062 SCV000931334 likely pathogenic Rasopathy 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 260 of the RAF1 protein (p.Thr260Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Noonan syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). The observation of one or more missense substitutions at this codon (p.Thr260Arg and p.Thr260Ile) in affected individuals suggests that this may be a clinically significant residue (PMID: 17603483, Invitae). 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 RCV000792062 SCV001361778 likely pathogenic Rasopathy 2020-07-08 criteria provided, single submitter clinical testing Variant summary: RAF1 c.779C>A (p.Thr260Lys) results in a non-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 251468 control chromosomes (gnomAD) )(ACMG PM2). 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.779C>A in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Since its previous evaluation by our laboratory, a ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, reporting it as de novo occurrence in an individual affected with Noonan syndrome (SCV000931334.1) (ACMG PM6). As parental testing was not conducted, this finding has not been independently corroborated at our laboratory. Other variants affecting the same codon or adjacent codons have been classified as pathogenic by our laboratory, in ClinVar database and reported in HGMD database as disease-associated (e.g. S259P, T260P, T260R, P261A, P261S, P261R, P261L), suggesting a possible mutational hotspot important for protein function (ACMG PM5). Nevertheless, at least one variant affecting the same codon (c.779C>T, p.Thr260Ile) is classified as VUS in ClinVar by the ClinGen RASopathy Variant Curation Expert Panel. Based on the evidence outlined above, the variant was re-classified as likely pathogenic.
Baylor Genetics RCV001330997 SCV001522880 pathogenic Noonan syndrome 5 2020-07-21 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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