Gene Validity Classification Summary

Gene/Disease Pair:

ACTG1 : nonsyndromic genetic deafness

HGNC:144 | MONDO_0019497
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss EP
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 2
4
4
Cabanillas R et al. 2018 Jul 9 (PMID:29986705);
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 23
7.2
7
Zhu M et al. 2003 Nov (PMID:13680526); van Wijk E et al. 2003 Dec (PMID:14684684); Rendtorff ND et al. 2006 Oct (PMID:16773128); Morín M et al. 2009 Aug 15 (PMID:19477959); de Heer AM et al. 2009 May (PMID:19548389); Liu P et al. 2008 Sep (PMID:18804074); Miyagawa M et al. 2013 Oct 9 (PMID:24130743); Miyagawa M et al. 2015 May (PMID:25792668); Baek JI et al. 2012 Sep 3 (PMID:22938506); Mutai H et al. 2013 Oct 28 (PMID:24164807); Park G et al. 2013 Mar 18 (PMID:23506231); Vona B et al. 2014 Dec (PMID:24875298); Wei Q et al. 2014 Nov 12 (PMID:25388789); Cabanillas R et al. 2018 Jul 9 (PMID:29986705); Lee CG et al. 2018 Jun (PMID:29620237); Wang L et al. 2018 Jun (PMID:30599039);
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   Summed LOD Family Count 3 3  
Candidate gene sequencing 24.22 7
Zhu M et al. 2003 Nov (PMID:13680526); van Wijk E et al. 2003 Dec (PMID:14684684); Rendtorff ND et al. 2006 Oct (PMID:16773128); de Heer AM et al. 2009 May (PMID:19548389); Wang L et al. 2018 Jun (PMID:30599039);
Exome/genome or all genes sequenced in linkage region 6.32 2
Zhu M et al. 2003 Nov (PMID:13680526); Park G et al. 2013 Mar 18 (PMID:23506231);
Total Summed LOD Score 30.54    
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
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 2 1 1
Belyantseva IA et al. 2009 Jun 16 (PMID:19497859); Perrin BJ et al. 2010 Oct 14 (PMID:20976199);
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) 1

 


 

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 1 13 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
01/10/2019
EXPERT CURATION (DATE)
Definitive
01/07/2019
EVIDENCE SUMMARY
The ACTG1 gene has been reported in cases of autosomal dominant nonsyndromic hearing loss (ADNSHL) DFNA20/26 with or without vestibular involvement and autosomal dominant Baraitser-Winter syndrome (BWS). Per criteria outlined by the ClinGen Lumping and Splitting Working group, while the molecular mechanism is not yet fully understood, individual variants appear to segregate with specific phenotypes and we have therefore split curations for the disease entities BWS and ADNSHL. ACTG1 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2003 (Zhu et al., PMID: 13680526). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental evidence. MIssense variants in this gene have been reported in at least 24 probands with ADNSHL in 15 publications (Zhu et al., 2003 PMID: 13680526; van Wijk et al., 2003 PMID: 14684684; Rendtorff et al., 2006 PMID: 16773128; Morin et al., 2009 PMID: 19477959; de Heer et al., 2009 PMID: 19548389; Liu et al., 2008 PMID: 18804074; Miyagawa et al., 2013 PMID: 24130743; Miyagawa et al., 2015 PMID: 25792668; Baek et all., 2013 PMID: 22938506; Park et al., 2013 PMID: 23506231; Vona et al., 2014 PMID: 24875298; Wei et al., 2014 PMID: 25388789; Cabanillas et al., 2018 PMID: 29986705; Lee et al., 2018 PMID: 29620237; Wang et al. 2018 PMID: 30599039). Variants in this gene segregated with disease in >100 additional family members. Although most de novo variants are seen in cases of BWS due to reduced reproductive fitness, de novo variants have been observed in individuals with ADNSHL (LMM unpublished data; Cabanillas et al. 2018 PMID: 29986705; Wang et al. 2018 PMID: 29357087). No loss-of-function variants have been reported in affected individuals, and one individual with a large deletion on chromosome 17 encompassing the ACTG1 gene did not have any of the major features of BWS including hearing loss (Riviere et al. 2012 PMID: 22366783). Additionally, no changes in protein levels of ACTG1 in patient cell lines containing pathogenic variants in ACTG1 were observed (Riviere et al. 2012 PMID: 22366783). These data suggest haploinsufficiency is not a mechanism of either ADNSHL or BWS and suggest both disorders may be due to gain-of-function through two distinct effects. Yeast models support functional effects of some of the reported hearing loss-causing variants (Bryan et al. 2006 PMID: 16690605, Bryan et al. 2009 PMID: 19419963; Morin et al., 2009 PMID: 19477959), and there is evidence that the amino acid position 118 is a mutational hot spot (Wang et al. 2018, PMID: 30599039). A homozygous ACTG1-null mouse model demonstrates progressive hearing loss which supports a role of the ACTG1 gene in hearing (Belyantseva et al. 2009, PMID: 19497859); however, this model constributed only limited experimental support given the mismatch in mutational mechanism to the human cases. Perrin et al., 2010 (PMID: 20976199) studied an ACTG1 conditional mouse model, however this model did not contribute additional data beyond the first mouse model given that the gene was knocked out as well. In summary, ACTG1 is definitively associated with autosomal dominant nonsyndromic hearing loss, based primarily on many human case observations with extensive segregation. 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 01/07/19.