ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.231G>A (p.Trp77Ter) (rs80338944)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211767 SCV000061488 pathogenic Rare genetic deafness 2017-06-22 criteria provided, single submitter clinical testing The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous with a second pathog enic variant in GJB2 (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padma 2009, Shafique 2014, LMM data). It has also been identified in 35/30 782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://g; dbSNP rs80338944), which is consistent with the carrie r frequency for recessive hearing loss in the general population. This nonsense variant leads to a premature termination codon at position 77, which is predicte d to lead to a truncated protein. Loss of function of the GJB2 gene is an establ ished disease mechanism in autosomal recessive nonsyndromic hearing loss. In add ition, another nonsense variant at an adjacent nucleotide position (c.230G>A) re sulting in the same amino acid change has also been reported in many individuals with hearing loss (Hwa 2003, Bazazzagedan 2012, Huang 2015). Several individual s have been reported with the p.Trp77X variant; however, the nucleotide change w as not described (Cheng 2005, Bajaj 2008, Bhalla 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing l oss based upon the predicted impact of the variant, and homozygosity or compound heterozygosity in multiple affected individuals.
Athena Diagnostics Inc RCV000711349 SCV000841703 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762904 SCV000893314 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000018524 SCV000917458 pathogenic Deafness, autosomal recessive 1A 2018-06-19 criteria provided, single submitter clinical testing Variant summary: GJB2 c.231G>A (p.Trp77X) 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 0.00015 in 246196 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00015 vs 0.025). c.231G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in homozygous and compound heterozygous state (e.g. Kelsell 1997, Santos 2005, Mani 2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000711349 SCV000936559 pathogenic not provided 2020-08-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Trp77*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acids of the GJB2 protein. This variant is present in population databases (rs80338944, ExAC 0.1%). This variant has been observed to segregate with nonsyndromic hearing loss in several families (PMID: 9139825, 25636251, 24840842). ClinVar contains an entry for this variant (Variation ID: 17001). A different truncation (p.Lys112Glufs*2) that lies downstream of this variant has been determined to be pathogenic (PMID: 9529365, 23141775). This suggests that deletion of this region of the GJB2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004393 SCV001163365 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
GeneDx RCV000711349 SCV001812639 pathogenic not provided 2020-07-14 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, 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: 33614373, 31980526, 18983339, 19465004, 20086291, 24840842, 30168495, 29086887, 29542069, 29921236, 24949729, 18941476, 9139825, 22975760, 25636251, 25087612)
OMIM RCV000018524 SCV000038806 pathogenic Deafness, autosomal recessive 1A 1997-05-01 no assertion criteria provided literature only
GeneReviews RCV000018524 SCV000041041 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000018524 SCV001453344 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing
University of Washington Center for Mendelian Genomics, University of Washington RCV001291332 SCV001479806 likely pathogenic Deafness, autosomal recessive no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000711349 SCV001958515 pathogenic not provided no assertion criteria provided clinical testing

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