Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KCNE1 : Jervell and Lange-Nielsen syndrome 2

HGNC:6240 | MONDO_0012871
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
3
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
3
Schulze-Bahr E et al. 1997 Nov (PMID:9354783); Duggal P et al. 1998 Jan 20 (PMID:9445165); Tyson J et al. 1997 Nov (PMID:9328483); Mönnig G et al. 2002 May (PMID:12132284);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.16 2
Schulze-Bahr E et al. 1997 Nov (PMID:9354783); Mönnig G et al. 2002 May (PMID:12132284);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.16    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 4
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Warth R et al. 2002 Mar (PMID:11832382); Kupershmidt S et al. 1999 Feb 05 (PMID:9933245);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Bianchi L et al. 1999 Aug (PMID:10400998); Splawski I et al. 2000 Sep 05 (PMID:10973849);
Models Non-human model organism 2 0 - 4 4 4 2 2
Letts VA et al. 2000 Oct (PMID:11003695); Vetter DE et al. 1996 Dec (PMID:8982171); Charpentier F et al. 1998 Oct 29 (PMID:9790991); Drici MD et al. 1998 Jul 13 (PMID:9670922);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 4 4 8 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Moderate
12/06/2018
EXPERT CURATION (DATE)
Moderate
06/22/2018
EVIDENCE SUMMARY
The KCNE1 gene has been associated with autosomal recessive Jervell and Lange-Nielsen Syndrome (JLNS) in 4 probands in 11 publications. At least 4 unique variants (missense, in-frame indel) have been reported in humans, and variants in this gene segregated with disease in 4 additional family members. KCNE1 was first associated with this disease in humans in 1997 (Tyson et al.). The mechanism for disease is homozygous loss of function causes irregular myocyte polarization from K+ channel activity leading to LQT and inner ear malformations causing HL and vestibular dysfunction (PMID: 9354783). This gene-disease association is supported by animal models, expression studies and in vitro functional assays showing the potential of variation in the protein to cause irregular heart conductivity and hearing loss. It is important to note that the KCNQ1 gene comprises a large percentage of the JLNS cases currently published in the literature and that though this appears to be a largely accepted gene-disease association, there is not quite enough case level information to reach a Definitive classification. However there is a large amount of experimental evidence showing the interaction between KCNE1 and KCNQ1 though this information was not scored. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.