Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.

ABSTRACT:

Background

The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Prior research shows that the deleterious effects and the subsequent molecular consequences of variants are often conserved among paralogous protein sequences within a gene family. Here, we systematically quantify on an exome-wide scale whether the existence of pathogenic variants in paralogous genes at a conserved position can serve as evidence for the pathogenicity of a new variant. For the gene family of voltage-gated sodium channels, where variants and expert-curated clinical phenotypes are available, we also assess whether phenotype patterns of multiple disorders for each gene are conserved across variant positions within the gene family.

Results

SUBMITTER: Brunger T 

PROVIDER: S-EPMC12235991 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature