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

Total submissions: 7

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
Division of Genomic Diagnostics,The 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	2018-11-28	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 247408 control chromosomes (gnomAD and publications). The variant, c.176_191del16, has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, both compound heterozygotes and homozygotes (Abe_2000, Kudo_2000, Snoeckx_2005, Dai_2009, Miyagawa_2013). These data indicate that the variant is very likely to be associated with disease. One functional study showed that the mutant protein cannot form gap junctions in the plasma membrane and was retained in the endoplasmic reticulum, suggesting that ER stress (ERS) and subsequent ERS-induced cell death may be responsible for hearing loss caused by this GJB2 truncation mutation (Zhang_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000725553	SCV000951165	pathogenic	not provided	2018-10-02	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.
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