Gene Validity Curation

LMAN1 - factor V and factor VIII, combined deficiency of, type 1

Gene: LMAN1 (HGNC:6631)
Classification - 11/27/2019
Disease: factor V and factor VIII, combined deficiency of, type 1 (MONDO_0009206)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: LMAN1 was first reported in relation to autosomal recessive factor V and factor VIII, combined deficiency in 1998 (Nichols WC, et al., 1998, PMID: 9546392). At least 38 unique variants (mostly nonsense and frameshift) 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 15 probands in 3 publications (PMIDs: 9546392, 15876275, 9546392). Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism or disease is homozygous loss of function. This gene disease association is supported by its biochemical function as a cargo receptor for the ER-to-Golgi transport of factor V and factor VIII (PMID: 10551804), its interaction with MCFD2 (PMID: 15886209) which is also implicated in this disease, and a knockout mouse model (PMID: 21795745) that also exhibits reductions of both factor V and factor VIII. In summary, LMAN1 is definitively associated with autosomal recessive inheritance of factor V and factor VIII, combined deficiency. 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 14
21
12
Nichols WC et al. 1998 Apr 3 (PMID:9546392); Neerman-Arbez M et al. 1999 Apr 1 (PMID:10090934); Sirachainan N et al. 2005 May (PMID:15876275);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Neerman-Arbez M et al. 1999 Apr 1 (PMID:10090934);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.81 1
Nichols WC et al. 1998 Apr 3 (PMID:9546392);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.81    
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
1
Moussalli M et al. 1999 Nov 12 (PMID:10551804);
Protein Interaction 0.5 0 - 2 1 0.5
Zhang B et al. 2005 Jul 8 (PMID:15886209);
Expression 0.5 0 - 2
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 1.5 1.5
Zhang B et al. 2011 Sep 22 (PMID:21795745);
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) 2.5

 


 

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 2.5 14.5 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
11/13/2019
EXPERT CURATION (DATE)
Definitive
11/27/2019
EVIDENCE SUMMARY
LMAN1 was first reported in relation to autosomal recessive factor V and factor VIII, combined deficiency in 1998 (Nichols WC, et al., 1998, PMID: 9546392). At least 38 unique variants (mostly nonsense and frameshift) 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 15 probands in 3 publications (PMIDs: 9546392, 15876275, 9546392). Variants in this gene segregated with disease in 3 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism or disease is homozygous loss of function. This gene disease association is supported by its biochemical function as a cargo receptor for the ER-to-Golgi transport of factor V and factor VIII (PMID: 10551804), its interaction with MCFD2 (PMID: 15886209) which is also implicated in this disease, and a knockout mouse model (PMID: 21795745) that also exhibits reductions of both factor V and factor VIII. In summary, LMAN1 is definitively associated with autosomal recessive inheritance of factor V and factor VIII, combined deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.