Gene Validity Curation

KLF11 - monogenic diabetes

Gene: KLF11 (HGNC:11811)
Classification - 02/12/2020
Disease: monogenic diabetes (MONDO_0015967)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Monogenic Diabetes EP
Evidence Summary: Evidence asserting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 1.5 points. KLF11 was first reported in relation to autosomal dominant monogenic diabetes in 2005 (Neve et al., 2005, PMID: 15774581). One of the original variants reported, p.Thr220Met (rs34336420), is now known to have a MAF of 0.04 in Africans (gnomAD) and is classified as benign/likely benign in ClinVar, and the second one p.Ala347Ser (rs121912645) has MAFs of 0.0005 and 0.0001 in Latino and European populations respectively. A common variant p.Gln62Arg (rs35927125, MAF in Europeans 0.12) was modestly associated with T2D in the original publication, but this is not borne out in the AMP T2D Portal (ExTexT2D exome chip Pval 0.08; type2diabetesgenetics.org). A rare variant (p.His418Gln) in this gene segregated with antibody negative childhood onset diabetes in 3 family members; a fourth carrier was said to be unaffected with limited information available (PMID 31124255), reducing evidence for segregation. Variants have shown in vitro effects on transcription and/or cofactor binding (PMID: 15774581, 31124255). In summary, there is a limited amount of genetic and experimental evidence, and most reported variants have allele frequencies in the general population that are too high to be considered causative. Therefore, the relationship of KLF11 with monogenic diabetes is disputed. Future evidence is needed to either support or refute the role KLF11 plays in this disease.
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 5
0.5
0.5
Neve B et al. 2005 Mar 29 (PMID:15774581); Ushijima K et al. 2019 May 23. (PMID:31124255); Kleinberger JW et al. 2018 Jun (PMID:29758564);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.2 1
Neve B et al. 2005 Mar 29 (PMID:15774581);
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 7
0
0
Florez JC et al. 2006 Dec (PMID:17130512); Gloyn AL et al. 2003 Feb (PMID:12540637);
Aggregate Variant Analysis 0-6 3
0
Neve B et al. 2005 Mar 29 (PMID:15774581); Tanahashi T et al. 2008 Jan (PMID:18199129); Kuroda E et al. 2008 Dec 27 (PMID:19122346);
Total Genetic Evidence Points (Maximum 12) 0.5
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
0.5
1
Neve B et al. 2005 Mar 29 (PMID:15774581);
Protein Interaction 0.5 0 - 2 1 0
Fernandez-Zapico ME et al. 2009 Dec 25 (PMID:19843526);
Expression 0.5 0 - 2 1 0.5
Neve B et al. 2005 Mar 29 (PMID:15774581);
Functional Alteration Patient cells 1 0 - 2 2
0
Non-patient cells 0.5 0 - 1 1 0
Lomberk G et al. 2013 Jun 14 (PMID:23589285);
Models Non-human model organism 2 0 - 4 4 1 0 0
Mathison A et al. 2015 Oct (PMID:26248217);
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) 1

 


 

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 0.5 1 1.5 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)
Limited
02/12/2020
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
02/12/2020
REASON(S) FOR CHANGE
Lack of evidence and allele frequencies in the general population that are too high to be considered causative led the experts to dispute the gene disease classification at this time.
EXPERT CURATION (DATE)
Disputed
02/12/2020
EVIDENCE SUMMARY
Evidence asserting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 1.5 points. KLF11 was first reported in relation to autosomal dominant monogenic diabetes in 2005 (Neve et al., 2005, PMID: 15774581). One of the original variants reported, p.Thr220Met (rs34336420), is now known to have a MAF of 0.04 in Africans (gnomAD) and is classified as benign/likely benign in ClinVar, and the second one p.Ala347Ser (rs121912645) has MAFs of 0.0005 and 0.0001 in Latino and European populations respectively. A common variant p.Gln62Arg (rs35927125, MAF in Europeans 0.12) was modestly associated with T2D in the original publication, but this is not borne out in the AMP T2D Portal (ExTexT2D exome chip Pval 0.08; type2diabetesgenetics.org). A rare variant (p.His418Gln) in this gene segregated with antibody negative childhood onset diabetes in 3 family members; a fourth carrier was said to be unaffected with limited information available (PMID 31124255), reducing evidence for segregation. Variants have shown in vitro effects on transcription and/or cofactor binding (PMID: 15774581, 31124255). In summary, there is a limited amount of genetic and experimental evidence, and most reported variants have allele frequencies in the general population that are too high to be considered causative. Therefore, the relationship of KLF11 with monogenic diabetes is disputed. Future evidence is needed to either support or refute the role KLF11 plays in this disease.