ClinVar

Description

Variant summary: RIT1 c.268A>G (p.Met90Val) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.268A>G has been reported in the literature as a de-novo occurrence in multiple fetal cases affected with Noonan Syndrome And Related Conditions (example, Milosavljevic_2016, Quinan-Jones_2019, Becher_2020, Stuurman_2019, Petrovski_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased activation of ERK signaling supporting a gain of function outcome (Buschenfelde_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.