Properties of incompletely penetrant cardiomyopathy-associated genome variants

Aim. To study and describe the properties of nucleotide sequence variants with incomplete penetrance associated with various cardiomyopathies.

Material and methods. The study used penetrance data of genome variants from a previously published study. The variants were annotated using Ensembl VEP, as well as information from the gnomAD, ClinVar, and dbNSFP databases.

Results. For all datasets, significant correlations of penetrance (Spearman correlation coefficient from -0,75 to -0,90) with the population frequency of variants in the gnomAD database were obtained. Variants with low penetrance values were enriched in variants of unknown significance. Most of the low-penetrance variants were missense substitutions. High-penetrance values were enriched in variants classified as pathogenic, most of which were frameshift variants. Significant correlations were obtained with weights calculated by different computational methods for predicting variant pathogenicity. For all data sets, the penetrance value was significantly correlated with the predictions of four following methods: CADD, BayesDel with and without frequency, and ClinPred.

Conclusion. For the first time, a relationship of the population frequency, type and pathogenicity prediction of a variant with the penetrance value was shown.

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