Gene Validity Curation

L1CAM - L1 syndrome

Gene: L1CAM (HGNC:6470)
Classification - 10/02/2019
Disease: L1 syndrome (MONDO_0017140)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism
Evidence Summary: Variants in L1CAM have been observed in individuals with L1 syndrome (includes brain abnormalities, intellectual disability, and movement problems), hydrocephalus, and Hirschsprung disease. These phenotypic features are only present in males. L1CAM was first reported in relation to the constellation of phenotypic features related to X-linked recessive L1 syndrome in 1992 (Rosenthal et al., 1303258). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.The mechanism for disease is hemizygous loss of function.There have been over 200 L1CAM mutations reported, including nonsense, frameshift, splicing, and missense variants, as well as large duplications and deletions (19846429, 9268105, 12725590, 10797421). Variants in this gene segregated with disease in at least 40 additional family members. This gene-disease association is supported by animal models (19565280). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. In summary, L1CAM is definitively associated with X-linked recessive L1 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 Intellectual Disability and Autism Gene Curation Expert Panel on 10/2/2019 (SOP Version 7).
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 4
6
6
Vos YJ et al. 2010 Mar (PMID:19846429);
Proband with predicted or proven null variant 1.5 0-2 10 8 6.5 6.5
Vos YJ et al. 2010 Mar (PMID:19846429);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
1.5
1.5
Vos YJ et al. 2010 Mar (PMID:19846429); Ruiz JC et al. 1995 Jul (PMID:7562969);
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 1 1  
Candidate gene sequencing 3.31 1
Ruiz JC et al. 1995 Jul (PMID:7562969);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.31    
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
Protein Interaction 0.5 0 - 2
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
Tapanes-Castillo A et al. 2010 Feb (PMID:19565280);
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) 1.5

 


 

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 1.5 13.5 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
10/02/2019
EXPERT CURATION (DATE)
Definitive
10/02/2019
EVIDENCE SUMMARY
Variants in L1CAM have been observed in individuals with L1 syndrome (includes brain abnormalities, intellectual disability, and movement problems), hydrocephalus, and Hirschsprung disease. These phenotypic features are only present in males. L1CAM was first reported in relation to the constellation of phenotypic features related to X-linked recessive L1 syndrome in 1992 (Rosenthal et al., 1303258). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.The mechanism for disease is hemizygous loss of function.There have been over 200 L1CAM mutations reported, including nonsense, frameshift, splicing, and missense variants, as well as large duplications and deletions (19846429, 9268105, 12725590, 10797421). Variants in this gene segregated with disease in at least 40 additional family members. This gene-disease association is supported by animal models (19565280). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. In summary, L1CAM is definitively associated with X-linked recessive L1 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 Intellectual Disability and Autism Gene Curation Expert Panel on 10/2/2019 (SOP Version 7).