Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

LZTR1 : Noonan syndrome

HGNC:6742 | MONDO_0018997
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: RASopathy
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
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
6
8.75
Johnston JJ et al. 2018 Feb 22. (PMID:29469822);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
2.75
Johnston JJ et al. 2018 Feb 22. (PMID:29469822);
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) 8.75
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 8.75 0 8.75 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
07/24/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
07/24/2018
REASON(S) FOR CHANGE
Only one publication
EXPERT CURATION (DATE)
Limited
07/24/2018
EVIDENCE SUMMARY
Only one publication has implicated LZTR1 with autosomal recessive Noonan syndrome, and though the evidence suggests enough points to classify the association as Moderate, this classification was downgraded to Limited (Johnston et al., 2018). The study describes 17 unique variants (predicted LOF) segregating in12 families in an autosomal recessive, manner, however there is currently no functional evidence to implicate the impact of these variants on the protein or to implicate that this gene causes Noonan syndrome or any other RASopathy. Of note: it appears that biallelic LOF is the primary mechanism of LZTR1-related recessive Noonan syndrome, but dominant negative variants can also cause the disease to segregate in a dominant manner.