Curating the Clinical Genome 2024 ePoster Gallery-Structural and Functional Assessment of Patient-associated Variants in KCNMA1

Structural and Functional Assessment of Patient-associated Variants in KCNMA1

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The document discusses the assessment of patient-associated variants in the KCNMA1 gene, associated with a neurological disorder. While only two variants have been confirmed as causative, this study mapped 82 variants within the BK potassium channel protein. They identified 18 loss-of-function (LOF) and 3 gain-of-function (GOF) variants, with LOF variants clustering in specific regions of the channel linked to its activity. By using pathogenicity algorithms and structural parameters, a new algorithm called KCNMA1 Meta Score (KMS) was developed, showing improvement in identifying pathogenic variants compared to standard algorithms. The KMS algorithm was found to be particularly effective in reclassifying certain variants of uncertain significance (VUS) as potentially pathogenic or nonpathogenic. The study concludes that the KMS algorithm has the potential to enhance genetic-based algorithms in identifying disease-causing mutations. By incorporating structural features and cutoff values derived from a training dataset, the KMS algorithm offers a more comprehensive assessment of variants affecting BK channel function, leading to a re-evaluation of the pathogenicity of certain VUS residues.

Keywords

KCNMA1 gene

neurological disorder

BK potassium channel protein

loss-of-function variants

gain-of-function variants

KCNMA1 Meta Score

pathogenicity algorithms

structural parameters

variants of uncertain significance

disease-causing mutations