ClinVar

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 312 of the GUCY2D protein (p.Thr312Met). This variant is present in population databases (rs61749673, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GUCY2D-related conditions (PMID: 15691574, 16205573, 19959640, 31964843, 34048777). ClinVar contains an entry for this variant (Variation ID: 98610). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. This variant disrupts the p.Thr312 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been observed in individuals with GUCY2D-related conditions (PMID: 26047050), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.