ClinVar

Description

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 394 of the GCM2 protein (p.Tyr394Ser). This variant is present in population databases (rs142287570, gnomAD 1.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hyperparathyroidism and/or parathyroid adenomas (PMID: 29264504, 30624640, 35038313). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 29264504). ClinVar contains an entry for this variant (Variation ID: 355008). 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 GCM2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCM2 function (PMID: 29264504, 35038313). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.