ClinVar Genomic variation as it relates to human health

Variant summary: RIT1 c.229G>A (p.Ala77Thr) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes. c.229G>A has been reported in the literature as a de-novo occurrence in multiple individuals affected with Noonan Syndrome (example, PMID: 26757980, 26714497). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 26714497). The most pronounced variant effect results in significantly enhanced ELK transactivation, confirming the gain-of function mechanism of disease. Five 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate that A77T acts as a gain-of-function variant, causing increased Elk1 activation and enhanced cJun transcription (Yaoita et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 183403; ClinVar); This variant is associated with the following publications: (PMID: 27109146, 27101134, 26714497, 26757980, 30692697, 29402968, 33726816)

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the RIT1 protein (p.Ala77Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26714497, 26757980, 27101134, 29402968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183403). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. Experimental studies have shown that this missense change affects RIT1 function (PMID: 26714497). For these reasons, this variant has been classified as Pathogenic.

PP3, PM2, PM6_strong, PS3_supporting, PS4

The RIT1 c.280G>A variant is predicted to result in the amino acid substitution p.Ala94Thr. This variant has also been referred to as p.Ala77Thr in literature. This variant has been reported in multiple individuals with Noonan syndrome; three times as a de novo event and once transmitted from an affected parent (Yaoita et al. 2016. PubMed: 26714497; Cavé et al 2016. PubMed ID: 26757980; Kouz et al 2016. PubMed ID: 27101134). Different missense variants that affect the same amino acid (p.Ala94Pro, p.Ala94Ser) have also been reported to be causative for Noonan spectrum disorders (Chen et al. 2014. PubMed ID: 25049390; Yaoita. 2016. PubMed ID: 26714497). In addition, it has been identified in multiple individuals tested for Noonan spectrum disorders in our internal database. This variant is interpreted as pathogenic. This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.