Accepted_test

The study investigates discrepancies in interpreting genetic variations linked to rare diseases. Despite published guidelines, labs sometimes disagree on a variant's clinical significance. We analyzed ClinVar data to identify genes with variants for which conflicting interpretations  of pathogenicity have been reported. The analysis revealed that a significant portion (78%) of disease-linked genes contain variants with conflicting interpretations. Interestingly, genes enriched with such variants tended to be structurally complex, with more exons and longer transcripts. These genes were also associated with a higher number of diseases, often inherited in an autosomal dominant mode. Notably, these genes were enriched for functions related to muscle structure and function. These findings suggest a link between complex genes, diverse disease associations, and difficulty in variant interpretation. The phenomenon of "phenotypic heterogeneity" might explain the disagreements, as variations in the same gene could cause different diseases or varying severity. Understanding these gene characteristics could help develop additional rules for interpreting variants in such  genes, ultimately improving consistency in clinical practice.