ClinVar

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 102 of the MPL protein (p.Arg102His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 32703794). ClinVar contains an entry for this variant (Variation ID: 988868). 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 MPL protein function. This variant disrupts the p.Arg102 amino acid residue in MPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11972523, 16470591, 21659346, 28859041). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.