Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GPSM2 : Chudley-McCullough syndrome

HGNC:29501 | MONDO_0011411
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count 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 11
10.5
10.5
Walsh T et al. 2010 Jul 09 (PMID:20602914); Yariz KO et al. 2012 Mar (PMID:21348867); Doherty D et al. 2012 Jun 08 (PMID:22578326); Almomani R et al. 2013 May (PMID:23494849); Hamzeh AR et al. 2016 Jun (PMID:27180139);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 2.4 2.4  
Candidate gene sequencing 3 1
Yariz KO et al. 2012 Mar (PMID:21348867);
Exome/genome or all genes sequenced in linkage region 4.24 1
Walsh T et al. 2010 Jul 09 (PMID:20602914);
Total Summed LOD Score 7.24    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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 Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Walsh T et al. 2010 Jul 09 (PMID:20602914); Bhonker Y et al. 2016 Feb (PMID:26662512);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Mauriac SA et al. 2017 Apr 07 (PMID:28387217);
Models Non-human model organism 2 0 - 4 4 2 3 3
Mauriac SA et al. 2017 Apr 07 (PMID:28387217); Bhonker Y et al. 2016 Feb (PMID:26662512);
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) 4.5

 


 

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 12 4.5 16.5 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
11/27/2018
EXPERT CURATION (DATE)
Definitive
05/01/2018
EVIDENCE SUMMARY
The relationship between GPSM2 and autosomal recessive Chudley-McCullough syndrome was evaluated using the ClinGen Clinical Validity Framework as of 11/16/2017. Variants in GPSM2 were first reported in humans with this disease as early as 2010 (Walsh et al.). At least 8 nonsense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 11 probands in 5 publications (23494849, 22578326, 27180139, 20602914, 21348867). Variants in this gene segregated with disease in 12 additional family members. Auditory testing and brain scans have lead to the diagnosis of Chudley-McCullough syndrome in each of these patients. This gene-disease association is supported by relevant expression studies and two mouse models. In summary, GPSM2 is definitively associated with autosomal recessive Chudley-McCullough syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 5/1/2018.