ClinVar

Description

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 869 of the FANCA protein (p.Gln869Pro). This variant is present in population databases (rs780825099, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 15643609, 17924555, 29098742; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 215981). 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 FANCA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 16720839, 17924555). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.