Submissions for variant NM_004004.6(GJB2):c.176_191del (p.Gly59fs) (rs750188782)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000725553	SCV000337719	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000374903	SCV000599736	pathogenic	Deafness, autosomal recessive 1A	2017-05-09	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000374903	SCV000917455	pathogenic	Deafness, autosomal recessive 1A	2020-12-10	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.176_191del16 (p.Gly59AlafsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 252656 control chromosomes (gnomAD and publications). c.176_191del16 has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, in both compound heterozygous and homozygous states (e.g. Abe_2000, Kudo_2000, Snoeckx_2005, Dai_2009, Miyagawa_2013, Shi_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, showing that the mutant protein was unable to form gap junctions with the plasma membrane, leading to retention in the endoplasmic membrane (ER) and suggesting that ER stress (ERS) and subsequent ERS-induced cell death may be reponsible for the hearing loss associated with this mutation (e.g. Zhang_2010, Shi_2018). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000725553	SCV000951165	pathogenic	not provided	2019-09-05	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the GJB2 gene (p.Gly59Alafs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acids of the GJB2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in many individuals with autosomal recessive nonsyndromic hearing loss, and is commonly found in affected individuals of East Asian descent (PMID: 10633133, 19125024, 19366456, 24224790, 26043044). ClinVar contains an entry for this variant (Variation ID: 284906). Experimental studies have shown that this variant results in a truncated protein produce that does not localize properly when expressed in cell culture (PMID: 20095872). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (such as p.Leu79Cysfs*3 and p.Tyr97*) have been determined to be pathogenic (PMID: 15070423, 19371219, 22747691, 26061264). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000725553	SCV001143661	pathogenic	not provided	2018-11-14	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001000906	SCV001157989	pathogenic	not specified	2018-11-07	criteria provided, single submitter	clinical testing	The GJB2 c.176_191del; p.Gly59fs variant (rs750188782) is associated with autosomal recessive nonsyndromic hearing loss (Abe 2000, Davoudi-Dehaghani 2014, Han 2008, Zhang 2010) and is reported as one of the most common pathogenic GJB2 variants in Chinese populations (Zhang 2010). This variant is classified as pathogenic in ClinVar (Variation ID: 284906). It is found in the general population with an overall allele frequency of 0.001% (3/246064 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 16 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Abe S et al. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet. 2000 Jan;37(1):41-3. Davoudi-Dehaghani E et al. Reporting the presence of three different diseases causing GJB2 mutations in a consanguineous deaf family. Int J Audiol. 2014 Feb;53(2):128-31. Han SH et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53(11-12):1022-8. Zhang Y et al. Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum. Acta Otolaryngol. 2010 Jul;130(7):799-803.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital	RCV000374903	SCV000902314	pathogenic	Deafness, autosomal recessive 1A	2019-02-26	no assertion criteria provided	case-control
Counsyl	RCV000374903	SCV001132399	likely pathogenic	Deafness, autosomal recessive 1A	2015-03-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000374903	SCV001453347	pathogenic	Deafness, autosomal recessive 1A	2020-09-16	no assertion criteria provided	clinical testing