NRAS NM_002524.4:c.173C>T, Thr58Ile

Variant summary: NRAS c.173C>T (p.Thr58Ile) 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 251312 control chromosomes (gnomAD). c.173C>T has been reported in the literature in at least one individual affected with Noonan Syndrome who inherited the variant from an unaffected father with mosaicism (Altmuller_2017). However, these data do not allow any conclusion about variant significance. When assayed experimentally in HEK293 cells, the variant showed constitutively enhanced ERK/AKT activation, confirming it was a gain-of-function variant (Altmuller_2017). Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the NRAS protein (p.Thr58Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 28594414). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1070042). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NRAS function (PMID: 28594414). For these reasons, this variant has been classified as Pathogenic.