ClinVar

Description

The R309H variant has been previously reported as a de novo potentially causal germline variant in an individual with brain malformations on MRI, including posterior-predominant pachygyria, corpus callosum abnormalities, small anterior vermis and short pons (Jamuar et al., 2014). R309H was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R309H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Based on the currently available information, GeneDx interprets R309H as a likely pathogenic variant; however, the possibility that it is benign cannot be excluded.