Gene Validity Classification Summary

Gene/Disease Pair:

ALG13 : undetermined early-onset epileptic encephalopathy

HGNC:30881 | MONDO_0018614
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Epilepsy EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
20
12
de Ligt J et al. 2012 Nov 15 (PMID:23033978); Epi4K Consortium et al. 2013 Sep 12 (PMID:23934111); Dimassi S et al. 2016 Feb (PMID:26138355); Kobayashi Y et al. 2016 Mar (PMID:26482601); Michaud JL et al. 2014 Sep 15 (PMID:24781210); Smith-Packard B et al. 2015 Mar 3 (PMID:25732998); Hamici S et al. 2017 Oct (PMID:28778787); Bastaki F et al. 2018 Jan (PMID:28940310); Ortega-Moreno L et al. 2017 Nov 30 (PMID:29190809);
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
0
0
Hino-Fukuyo N et al. 2015 Jun (PMID:25877686); Farwell KD et al. 2015 Jul (PMID:25356970);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 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
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) 0

 


 

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 0 12 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
04/19/2018
EXPERT CURATION (DATE)
Definitive
04/26/2018
EVIDENCE SUMMARY
A precuration for the ALG13 gene, performed by the Epilepsy Gene Curation Expert Panel, lead to the curation of ALG13 in association with X-linked 'Undetermined Early-onset Epileptic Encephalopathy'. The gene-disease association of ALG13 and X-linked Undetermined Early-onset Epileptic Encephalopathy has been classified as Definitive. A p.Asn107Ser variant in ALG13 has been observed de novo in at least ten female probands, with onset of seizures within one to eight months of age. Additional maternally inherited missense variants in ALG13 have been reported in males with a variety of phenotypes, including seizures, bilateral optic nerve atrophy, and intellectual disability. One male individual (Timal et al. 2012, PMID 22492991) was reported to have an ALG13 missense variant and Congenital disorder of glycosylation, type 1, however no other papers besides Timal 2012 test for enzyme activity by way of serum transferrin isofocusing in males with ALG13 variants. One female proband with the de novo p.Asn107Ser variant was tested by transferrin isoform analysis and found to have normal results, indicating that the mechanism of disease is different between males and females (Dimassi et al. 2016; PMID 26138355). At this time no functional data exists to propose a mechanism of disease.