ClinVar

Description

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 20 of the MVK protein (p.His20Pro). This missense change has been observed in individual(s) with autosomal recessive mevalonate kinase deficiency (PMID: 10369261, 10896296, 16835861). 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: 11931). 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 MVK protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261). This variant disrupts the p.His20 amino acid residue in MVK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313769, 15536479, 27213830, 28501347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.