Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins NTD LLC |
RCV000725553 | SCV000337719 | pathogenic | not provided | 2015-11-24 | criteria provided, single submitter | clinical testing | |
Genomic Diagnostic Laboratory, |
RCV000374903 | SCV000599736 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2017-05-09 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000374903 | SCV000917455 | pathogenic | Autosomal recessive nonsyndromic hearing loss 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 | 2021-10-09 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gly59Alafs*18) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acid(s) 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 premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 10633133, 19125024, 19366456, 24224790, 26043044). ClinVar contains an entry for this variant (Variation ID: 284906). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 20095872). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu79Cysfs*3, p.Tyr97*) have been determined to be pathogenic (PMID: 15070423, 19371219, 22747691, 26061264). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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, |
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. |
Gene |
RCV000725553 | SCV001790968 | pathogenic | not provided | 2020-12-02 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation, as the last 168 amino acids are replaced with 17 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29871260, 30275481, 31541171, 31564438, 30146550, 30036422, 30693673, 29665173, 30589569, 30282152, 19366456, 25388846, 28489599, 28583500, 29741433, 10607953, 26037344, 19125024, 24100002, 24737404, 26043044, 19043807, 10633133, 24224790, 25266519, 20095872) |
Genetic Testing Center for Deafness, |
RCV000374903 | SCV000902314 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2019-02-26 | no assertion criteria provided | case-control | |
Counsyl | RCV000374903 | SCV001132399 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2015-03-23 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000374903 | SCV001453347 | pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2020-09-16 | no assertion criteria provided | clinical testing |