rs397514481

Description

The PLCB4 c.1862G>A (p.Arg621His) variant is a missense variant. Across a selection of the available literature, the p.Arg621His variant has been identified in a heterozygous state in at least seven individuals of a multi-generational family segregating with auriculocondylar syndrome (ACS), and in one sporadic case of ACS, in which the variant occurred in a de novo state (Rieder et al. 2012; Gordon et al. 2013). The p.Arg621His variant was not found in 10758 control alleles and is not reported in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare (Rieder et al. 2012). The p.Arg621His variant is highly conserved through evolution and is located in a catalytic domain of the PCLB4 protein in a region described as a hotspot for missense variation associated with ACS (Gordon et al. 2013). Additionally, at least two more missense variants with different amino acid alterations at the Arg61 residue have been reported in the literature in affected individuals (Gordon et al. 2013). Based on the collective evidence and application of the ACMG criteria, the p.Arg621His variant is classified as pathogenic for auriculocondylar syndrome.