Gene Validity Classification Summary

Gene/Disease Pair:

LARS2 : Perrault syndrome

HGNC:17095 | MONDO_0017312
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss 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
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
1.5
8
Pierce SB et al. 2013 Apr 4 (PMID:23541342);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
6.5
Pierce SB et al. 2013 Apr 4 (PMID:23541342); Lerat J et al. 2016 Dec (PMID:27650058); Demain LA et al. 2017 Feb (PMID:26970254); Soldà G et al. 2016 Apr (PMID:26657938); Zazo Seco C et al. 2017 Feb (PMID:28000701); Kosaki R et al. 2018 Feb (PMID:29205794); Zerkaoui M et al. 2017 Oct (PMID:28832386);
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
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
1
Riley LG et al. 2015 Nov 5 (PMID:26537577);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Nishio SY et al. 2017 May (PMID:28263850);
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
Pierce SB et al. 2013 Apr 4 (PMID:23541342);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
0.5
Pierce SB et al. 2013 Apr 4 (PMID:23541342);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

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 8 2.5 10.5 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
06/27/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
06/27/2018
REASON(S) FOR CHANGE
An additional internal case at the Laboratory for Molecular Medicine involves two young sisters with profound sensorineural hearing loss, who are compound heterozygous for a missense variant and an exon 22 deletion. Experts decided to upgrade the classification to Strong.
EXPERT CURATION (DATE)
Strong
06/27/2018
EVIDENCE SUMMARY
The LARS2 gene has been associated with autosomal recessive Perrault syndrome using the ClinGen Clinical Validity Framework as of 6/26/2018. This association was made using case-level data only. At least 10 variants (missense, frameshift) have been reported in humans. LARS2 was first associated with this disease in humans as early as 2013 (Pierce et al.). Association is seen in at least 9 probands in 7 publications (23541342, 27650058, 26970254, 26657938, 28832386, 28000701, 29205794). Variants in this gene segregated with disease in 7 additional family members. An additional internal case at the Laboratory for Molecular Medicine involves two young sisters with profound sensorineural hearing loss, who are compound heterozygous for a missense variant and an exon 22 deletion. This gene-disease association is supported by relevant expression studies. In summary, after expert review, there is strong evidence to support the association between LARS2 amd autosomal recessive Perrault syndrome. Additional reports in humans are needed to reach a definitive classification. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.