ClinVar

Description

The p.His310Arg variant in the KCNA2 gene has previously been reported de novo in an individual with severe intellectual disability, motor delay, absent speech, epilepsy, unclassified autism, pervasive behavioral problems and hypertonia (Leiden Open Variation Database (LOVD); personal communication). The p.His310Arg variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant is located in a conserved, functional domain (S4 segment of the voltage sensor domain), it is not located in the N-terminal region of the S4 segment where previously reported variants have clustered. However, the KCNA2 gene has fewer missense variants in the general population than expected and a low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.His310Arg variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.His310Arg variant as likely pathogenic for disease in an autosomal dominant manner [ACMG/AMP guidelines used: PM6, PM2, PP2, PP3].