Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

LZTR1 : Noonan syndrome

HGNC:6742 | MONDO_0018997
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
4
4
Yamamoto GL et al. 2015 Jun (PMID:25795793);
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
2
2
Yamamoto GL et al. 2015 Jun (PMID:25795793); Chen PC et al. 2014 Aug 5 (PMID:25049390);
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) 6
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 6 0 6 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)
Limited
07/25/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
07/25/2018
REASON(S) FOR CHANGE
See Evidence Summary
EXPERT CURATION (DATE)
Strong
07/25/2018
EVIDENCE SUMMARY
There is a strong association between alteration of the LZTR1 gene and the dominant NS phenotype. 5.5 points of genetic evidence are currently available in the literature. However, there were seven variants with confirmed de novo inheritance (SCV000778847, SCV000330730, SCV000491887, SCV000619636, SCV000778848, SCV000778849, SCV000778850) and one variant with unconfirmed de novo inheritance (SCV000568857) identified at GeneDx in individuals with features consistent with a RASopathy. Clinical features included short stature, pulmonary stenosis, lymphedema, atrial septal defect, developmental delay, hypertrophic cardiomyopathy, and/or dysmorphic facial features consistent with NS Therefore, the maximum amount of genetic evidence has been reached. However, given that there has only been one published study in Yamamoto 2015, and less than 3 years has passed since this publication, the association must remain at Strong(Yamamoto et al., 2015). This is an association that should be noted to move to Definitive with time, and further publication of the cases currently identified. Of note, several missense and other non-LOF variants have been identified to segregate in a dominant manner, while heterozygous LOF variants have been found in unaffected carriers in families with recessive NS, therefore, the suspected mechanism of disease in LZTR1 is dominant-negative. Further functional evidence is required to solidify this mechanism (Johnston et al., 2018).