Submissions for variant NM_002880.4(RAF1):c.779C>A (p.Thr260Lys)

dbSNP: rs869025501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792062	SCV000931334	pathogenic	RASopathy	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 260 of the RAF1 protein (p.Thr260Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 639302). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt RAF1 function with a positive predictive value of 95%. This variant disrupts the p.Thr260 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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].
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001330997	SCV005417142	likely pathogenic	Noonan syndrome 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PS2+PS4_Supporting+PM5