Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MARVELD2 : nonsyndromic genetic deafness

HGNC:26401 | MONDO_0019497
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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
Riazuddin S et al. 2006 Dec (PMID:17186462); Chishti MS et al. 2007 Dec 15 (PMID:18084694); Babanejad M et al. 2012 Oct (PMID:22903915); Yan D et al. 2016 Aug (PMID:27344577);
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) 12
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 0.5
Kitajiri S et al. 2014 Jul 25 (PMID:25063198);
Expression 0.5 0 - 2 1
Riazuddin S et al. 2006 Dec (PMID:17186462);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Kamitani T et al. 2015 Dec 18 (PMID:26677943); Nayak G et al. 2013 Sep (PMID:23979167);
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) 5.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5.5 17.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The MARVELD2 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/16/17. This association was made using case-level data. At least 7 variants (splice site, nonsense, frameshift) have been reported in humans. MARVELD2 was first associated with this disease in humans as early as 2006 (Riazuddin et al.​). Association is seen in at least 7 probands in 4 publications (17186462, 18084694, 22903915, 27344577). Variants in this gene segregated with disease in at least 38 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Many variants were shown to evade nonsense mediated decay and produce viable mRNA transcripts. Mice with the p.R500X variant seen in humans had hearing loss and while the mRNA did not undergo NMD, no protein product was detected in the inner ear tricellular tight junctions, where the WT protein localizes. This gene-disease association is also supported by a knock-out mouse model and relevant expression and protein interaction studies. In summary, MARVELD2 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/18.