Evidence map›Paper›PMID 29330128›Full record

ArticleHeart rhythm2018

Exploiting ion channel structure to assess rare variant pathogenicity.

Brett M Kroncke, Tao Yang, Prince Kannankeril, M Benjamin Shoemaker, Dan M Roden

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Heart rhythm, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Mutation-Specific Differences in Kv7.1 (International journal of molecular sciences · 2022
    Review
  2. How Functional Genomics Can Keep Pace With VUS Identification.Frontiers in cardiovascular medicine · 2022
    Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors.

Brett M KronckeDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Tao YangDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Prince KannankerilDepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
M Benjamin ShoemakerDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Dan M RodenDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: dan.roden@vanderbilt.edu.

Funding

Understanding and preventing HLA-associated drug reactionsP50GM115305 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI RODEN, DAN M · 2015 to 2019
$13.0M
VGER, the Vanderbilt Genome-Electronic Records ProjectU01HG008672 · NHGRI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI DENNY, JOSHUA C., RODEN, DAN M · 2015 to 2019
$5.1M
SCN5A mutations and dilated cardiomyopathyR01HL118952 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI RODEN, DAN M · 2014 to 2017
$1.6M
Atrial Fibrillation Susceptibility Due to Genetic Variation at Chromosome 4q25K23HL127704 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI SHOEMAKER, MOORE BENJAMIN · 2015 to 2019
$869k
SCN5A (Nav1.5): Predicting the Consequence of Missense Single- Nucleotide Polymorphisms.R00HL135442 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KRONCKE, BRETT M · 2019 to 2021
$741k
SCN5A (Nav1.5): Predicting the Consequence of Missense Single- Nucleotide Polymorphisms.K99HL135442 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KRONCKE, BRETT M · 2017 to 2018
$242k
High-throughput Discovery of Pathogenic Cardiac Sodium Channel VariantsF32HL137385 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI GLAZER, ANDREW M. · 2017 to 2019
$133k
NHGRI NIH HHS U01 HG008672NHLBI NIH HHS F32 HL137385NHLBI NIH HHS K23 HL127704NHLBI NIH HHS K99 HL135442NHLBI NIH HHS R00 HL135442NHLBI NIH HHS R01 HL118952NIGMS NIH HHS P50 GM115305
6 · The paper itself

Abstract

backgroundA 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants.

objectiveThe purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation.

methodsWe used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels.

resultsThe structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign.

conclusionProximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.

Indexed as

MutationAdolescentAdultBody Surface Potential MappingDNADNA Mutational AnalysisERG1 Potassium ChannelFemaleHumansKCNQ1 Potassium ChannelLong QT SyndromePedigreePhenotypeDNAERG1 Potassium ChannelKCNH2 protein, humanKCNQ1 Potassium ChannelInherited arrhythmiasKCNH2KCNQ1Long QTProtein structure

Identifiers

PMID29330128
PMCPMC5984725

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.