Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KCNQ1 : Jervell and Lange-Nielsen syndrome

HGNC:6294 | MONDO_0009078
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 6
10
12
Neyroud N et al. 1997 Feb (PMID:9020846); Uysal F et al. 2017 Oct 16 (PMID:29037160); Coto E et al. 2017 Mar (PMID:27868350); Sung JY et al. 2014 Sep (PMID:25187895); Qureshi SF et al. 2013 Sep-Oct (PMID:24206879);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
2
Uysal F et al. 2017 Oct 16 (PMID:29037160); Vyas B et al. 2016 Jun (PMID:27041150);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.2 1
Uysal F et al. 2017 Oct 16 (PMID:29037160);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 4 2
Neyroud N et al. 1997 Feb (PMID:9020846); Chang Q et al. 2015 Aug (PMID:26084842); Casimiro MC et al. 2001 Feb 27 (PMID:11226272); Nicolas M et al. 2001 Mar (PMID:11223304);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Casimiro MC et al. 2001 Feb 27 (PMID:11226272);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Chang Q et al. 2015 Aug (PMID:26084842);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

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 12 6 18 YES
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)
Definitive
12/06/2018
EXPERT CURATION (DATE)
Definitive
12/19/2017
EVIDENCE SUMMARY
The relationship between KCNQ1 and autosomal recessive Jervell and Lange-Nielsen Syndrome (JLNS) was evaluated using the ClinGen Clinical Validity Framework as of 12/11/2017. Variants in KCNQ1 were first reported in humans with this disease as early as 1997 (Neyroud et al., PMID 9020846). At least 11 unique variants (missense, in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data knockout mouse models, rescue in mice, as well as expression of KCNQ1 in the heart and inner ear (PMIDs: 11226272, 11223304, 26084842, 9020846). The mechanism for disease is homozygous LOF of the KCNQ1 gene causes JLNS though alterations have also been shown to cause Romano-Ward Syndrome in an AD manner (PMID: 29037160). Variants in this gene have been reported in at least 9 probands in 9 publications (PMIDs 29037160, 27041150, 9020846, 27868350, 25187895, 24206879). Variants in this gene segregated with disease in 2 additional family members. In summary, KCNQ1 is definitively associated with Jervell and Lange-Nielsen Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.