# Core A - Variant prioritization and curation core

> **NIH NIH U54** · NORTHWESTERN UNIVERSITY · 2021 · $230,066

## Abstract

PROJECT SUMMARY – CORE A
Variants in ion channel genes represent the most common genetic finding in severe pediatric epilepsies.
However, knowledge of the genetic landscape of channelopathy-associated epilepsy is incomplete, owing to
the rapid pace of variant discovery and the challenges of variant interpretation. Further, much of the existing
relevant knowledge is not widely available, including recently identified variants, associated clinical
phenotypes, protocols for variant functional analysis, and best practices for integrating functional, genetic, and
clinical data to assess pathogenicity and prognosis. The Variant Prioritization and Curation Core (Core A) will
modify and deploy an existing collaborative bioinformatics and variant curation platform to support the mission
of our Center. Core A will serve as an interface to ongoing NIH curation efforts, including ClinVar and ClinGen,
to ensure that functional data generated by the Center are enduring and fully accessible.
In Aim 1, we will catalog variants in the epilepsy-associated voltage-gated ion channel genes. To maximize the
utility of in vitro and in vivo functional studies performed in Projects 1-3, Core A will establish and maintain a
database of known epilepsy-associated variants in voltage-gated ion channel genes. We will assemble genetic
and phenotypic information from diverse sources including publications, locus-specific databases, previously
undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). In
Aim 2, we will prioritize variants in ion channel genes for functional evaluation. Ion channel gene variants of the
highest clinical importance and analytical validity will be selected for the high-throughput studies proposed in
Project 1. To identify which variants meet this standard, we will apply a range of criteria including established
American College of Medical Genetics and Genomics (ACMG) diagnostic rules and an advanced data-driven
algorithm that considers mutational ‘hot spots,’ gene family information, and regional intolerance. Based on the
applied criteria, we will prioritize 1,000 variants for functional evaluation over the 5-year funding period. In Aim
3, we will use functional data to iteratively refine variant classifications and diagnostic criteria. We will apply
results from the Center to propose improved classification rules for variants and work within the ClinGen
consortium to develop a gene/variant-based taxonomy of early onset epilepsy that harmonizes with the
International League Against Epilepsy (ILAE) classification and terminology. To ensure public access, Core A
members will expand their ongoing collaboration with the NIH-funded ClinGen consortium, and the ClinVar
archive by submitting all classified ion channel variants and key supporting evidence to ClinVar as an Expert
Panel. As part of this effort, we will augment existing ClinVar data elements to include data fields on variant
function using an ontol...

## Key facts

- **NIH application ID:** 10247553
- **Project number:** 5U54NS108874-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** EDWARD C COOPER
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $230,066
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247553

## Citation

> US National Institutes of Health, RePORTER application 10247553, Core A - Variant prioritization and curation core (5U54NS108874-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247553. Licensed CC0.

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