ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.230G>A (p.Trp77Ter)

dbSNP: rs104894395
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169604 SCV000221125 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2015-02-11 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000218259 SCV000271372 pathogenic Rare genetic deafness 2016-02-25 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 for a second pathoge nic variant in GJB2 (Hwa 2003, Bazazzagedan 2012, Huang 2015). This variant has not been reported in large population studies. This nonsense variant leads to a premature termination codon at position 77, which is predicted to lead to a tru ncated or absent protein. Loss of function of the GJB2 gene is an established di sease mechanism in autosomal recessive nonsyndromic hearing loss. In addition, a nother nonsense variant at an adjacent nucleotide position (c.231G>A) resulting in the same amino acid change has also been reported in many individuals with he aring loss (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padm a 2009, Shafique 2014). Several individuals have been reported with the p.Trp77 X variant; however, the nucleotide change was not described (Cheng 2005, Bajaj 2 008, Bhalla 2009). In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive hearing loss based upon the predicted impa ct of the variant and multiple occurrences in the homozygous state as well as in compound heterozygosity with pathogenic GJB2 variants in individuals with heari ng loss.
Labcorp Genetics (formerly Invitae), Labcorp RCV001382072 SCV001580694 pathogenic not provided 2024-01-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp77*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894395, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive nonsyndromic hearing loss (PMID: 12792423, 30146550). ClinVar contains an entry for this variant (Variation ID: 189176). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Lys112Glufs*2) have been determined to be pathogenic (PMID: 9529365, 23141775). 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.
Natera, Inc. RCV000169604 SCV001453345 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing

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