Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RPL10 : X-linked syndromic intellectual disability

HGNC:10298 | MONDO_0020119
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Intellectual Disability and Autism
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
2
2
Bourque DK et al. 2018 Feb (PMID:29066376);
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
1.5
1.5
Thevenon J et al. 2015 Aug (PMID:25846674); Zanni G et al. 2015 Dec (PMID:26290468); Klauck SM et al. 2006 Dec (PMID:16940977); Chiocchetti A et al. 2011 Jun (PMID:21567917); Brooks SS et al. 2014 Oct (PMID:25316788);
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) 3.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Brooks SS et al. 2014 Oct (PMID:25316788);
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 2.5
Brooks SS et al. 2014 Oct (PMID:25316788);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
1.5
Klauck SM et al. 2006 Dec (PMID:16940977); Brooks SS et al. 2014 Oct (PMID:25316788);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3

 


 

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 3.5 3 6.5 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)
Moderate
04/27/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
04/27/2018
REASON(S) FOR CHANGE
An additional 1.75 points calculated by weighted scoring for segregation brings the score to 8. The RPL10 gene has been implicated in X-linked syndromic intellectual disability. Missense variants, including one de novo missense, have been published in the literature. Both the p.Leu206Met and p.His213Gln variants reported by Klauck 2006 have been suggested to be benign by the rescue studies done by Brooks 2014. At this point, only a zebrafish model exists for the RPL10 and X-linked syndromic intellectual disability association. Experts in the Intellectual Disability/Austism Gene Curation Expert Panel have agreed on classifying this variant as Limitied, based on lack of convincing proband cases and lack of functional evidence/mouse models.
EXPERT CURATION (DATE)
Limited
04/27/2018
EVIDENCE SUMMARY
An additional 1.75 points calculated by weighted scoring for segregation brings the score to 8. The RPL10 gene has been implicated in X-linked syndromic intellectual disability. Missense variants, including one de novo missense, have been published in the literature. Both the p.Leu206Met and p.His213Gln variants reported by Klauck 2006 have been suggested to be benign by the rescue studies done by Brooks 2014. At this point, only a zebrafish model exists for the RPL10 and X-linked syndromic intellectual disability association. Experts in the Intellectual Disability/Austism Gene Curation Expert Panel have agreed on classifying this variant as Limitied, based on lack of convincing proband cases and lack of functional evidence/mouse models.