Gene Validity Classification Summary

Gene/Disease Pair:

MYH9 : MYH-9 related disease

HGNC:7579 | MONDO_0015912
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
Balduini CL et al. 2011 Jul (PMID:21542825);
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
Lalwani AK et al. 1997 May-Jun (PMID:9390828); Verver E et al. 2015 Jul (PMID:24890873); Hildebrand MS et al. 2006 Dec (PMID:17146397); Dantas VG et al. 2014 Oct (PMID:25505834);
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) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Franke JD et al. 2005 Jan 1 (PMID:15339844);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Mhatre AN et al. 2006 Sep (PMID:16862555);
Functional Alteration Patient cells 1 0 - 2 2
Pecci A et al. 2005 Nov 1 (PMID:16162639);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 6 4
Parker LL et al. 2006 May 26 (PMID:16630581); Suzuki N et al. 2013 Aug 20 (PMID:23976996); Zhang Y et al. 2012 Jan 5 (PMID:21908426);
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) 6



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 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The MYH9 gene definitively causes MYH9-Related Disorders, a class of autosomal dominant disorders characterized by congenital macrothrombocytopenia and variable leucocyte inclusion bodies, renal abnormalities, cataracts, and progressive sensorineural hearing loss. This association was assessed using the ClinGen Clinical Validity Framework as of 12/11/2017. Recent reviews report that missense variants are located at only 21 of the 1,960 amino acid residues of the protein (Balduini 2011, De Rocco 2013, Pecci 2014). Nonsense or frameshift variants of MYH9 have only been reported in the last exon of the gene. A genotype-phenotype correlation has been shown repeatedly (Dong 2005, Pecci 2008, Pecci 2014, Saposnik 2014). There are several reports of the p.Arg705His variant in MYH9 causing nonsyndromic hearing loss, DFNA17 (Lalwani 2000, Hildebrand 2006). However, no testing for the blood phenotype was reported in any affected individuals in these families, and at least two other individuals with the hematological features of MYH9-RD had the same variant (Verver 2015). These data suggest nonsyndromic hearing loss may not be a distinct entity from MYH9-RD. Hearing loss is not a fully penetrant feature of MYH9-RD; a review of cases indicated approximately 48% of patients have hearing loss (Pecci 2014). Individuals presenting with nonsyndromic hearing loss who are found to have a pathogenic variant in MYH9 should be tested for the other phenotypes of MYH9-RD. In vitro functional evidence indicates that disease-causing variants may act through different molecular mechanisms in different cell types (Franke 2005, Hu 2002, Pecci 2005), exhibiting a dominant-negative effect on wild-type protein in granulocytes and haploinsufficiency in megakaryocytes and platelets (Pecci 2005). Four knock-in mouse models harboring 3 different human variants in MYH9 fully recapitulated the human phenotype of MYH9-RD (Zhang 2012, Suzuki 2013). In summary, MYH9 is definitively associated with AD MYH9-RD. 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 2/20/2018.