Gene Validity Curation

FERMT3 - leukocyte adhesion deficiency 3

Gene: FERMT3 (HGNC:23151)
Classification - 08/28/2019
Disease: leukocyte adhesion deficiency 3 (MONDO_0013016)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: FERMT3 was first reported in relation to autosomal recessive leukocyte adhesion deficiency 3 in 2008 (Mory et al., PMID: 18779414). At least 15 unique variants (primarily nonsense, along with other LoF splicing and frameshift variants, and few inactivating missense variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 6 publications (PMIDs: 18779414, 19234463, 19234460, 19064721, 21441448, 22139635). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by the enhanced expression of FERMT3 in hematopoietic tissues, its biochemical function in integrin activation which is altered in patient cells but can be rescued, and a null mouse model which recapitulates both cellular defects and clinical phenotypes observed in human LAD-III patients. In summary, FERMT3 is definitively associated with autosomal recessive leukocyte adhesion deficiency 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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 7
13
12
Svensson L et al. 2009 Mar (PMID:19234463); Malinin NL et al. 2009 Mar (PMID:19234460); Kuijpers TW et al. 2009 May 7 (PMID:19064721); Robert P et al. 2011 May 1 (PMID:21441448); Harris ES et al. 2012 Mar (PMID:22139635);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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 1
0.5
2
Moser M et al. 2009 Mar (PMID:19234461);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1.5
Ussar S et al. 2006 Oct 1 (PMID:16876785);
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Svensson L et al. 2009 Mar (PMID:19234463); Malinin NL et al. 2009 Mar (PMID:19234460);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Moser M et al. 2008 Mar (PMID:18278053);
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 2 2
Svensson L et al. 2009 Mar (PMID:19234463); Malinin NL et al. 2009 Mar (PMID:19234460);
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
07/18/2019
EXPERT CURATION (DATE)
Definitive
08/28/2019
EVIDENCE SUMMARY
FERMT3 was first reported in relation to autosomal recessive leukocyte adhesion deficiency 3 in 2008 (Mory et al., PMID: 18779414). At least 15 unique variants (primarily nonsense, along with other LoF splicing and frameshift variants, and few inactivating missense variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 18 probands in 6 publications (PMIDs: 18779414, 19234463, 19234460, 19064721, 21441448, 22139635). Variants in this gene segregated with disease in two additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease relationship is supported by the enhanced expression of FERMT3 in hematopoietic tissues, its biochemical function in integrin activation which is altered in patient cells but can be rescued, and a null mouse model which recapitulates both cellular defects and clinical phenotypes observed in human LAD-III patients. In summary, FERMT3 is definitively associated with autosomal recessive leukocyte adhesion deficiency 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.