Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ACTG1 : Baraitser-winter syndrome 2

HGNC:144 | MONDO_0013812
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 6
Rivière JB et al. 2012 Feb 26 (PMID:22366783); Poirier K et al. 2015 Aug (PMID:26188271); Di Donato N et al. 2016 Oct (PMID:27240540);
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
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
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) 0



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 0 12 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The ACTG1 gene has been reported in both 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. The primary features of BWS include intellectual disability, trigonocephaly, hypertelorism, ptosis, and arched eyebrows, and secondary features include pachygyria/lissencephaly, coloboma, hearing loss, epilepsy, microphthalmia, agenesis or thickened corpus callosum (Yates et al. 2017 PMID: 27625340). The ACTG1 and autosomal dominant BWS relationship is supported by at least 11 de novo missense variants reported in at least 12 probands in 5 publications (Riviere et al. 2012 PMID: 22366783; Verloes et al. 2014 PMID: 25052316 ; Rainger et al. 2017 PMID: 28493397; Poirier et al. 2015 PMID: 26188271; Donato et al. 2016 PMID: 27240540). Additional cases have been reported, however parents were either not tested or not available for testing. 62% (8/13) of reported probands with a BWS diagnosis for whom clinical information was available had some degree of hearing loss, though severity, progressivity, and age-of-onset of hearing loss were variable. Variable expressivity has been reported in one family with hearing loss, seizures, estropia, and ocular coloboma (Kemerley et al. 2017 PMID: 27096712), as has isolated coloboma (Rainger et al. 2017 PMID: 28493397). In general, the association of de novo occurence with BWS is likely due to reduced reproductive fitness, however de novo variants have also been observed in individuals with ADNSHL (LMM unpublished data; Cabanillas et al. 2018 PMID: 29986705; Wang et al. 2018 PMID: 29357087). The existence of variant-specific phenotypes are supported by functional evidence in cell lines derived from BWS patients (Riviere et al. 2012 PMID: 22366783) and in yeast containing hearing loss-causing variants (Bryan et al. 2006 PMID: 16690605). 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 (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. In summary, ACTG1 is definitively associated with autosomal dominant Baraitser-Winter syndrome, primarily based upon many cases with de novo variation. 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.