ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.523_533del (p.Pro175fs) (rs876657693)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000213910 SCV000271374 pathogenic Rare genetic deafness 2016-04-07 criteria provided, single submitter clinical testing The p.Pro175fs variant in GJB2 has not been previously reported in individuals w ith hearing loss. This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 175 and leads to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncate d or unstable protein. In summary, this variant meets the criteria to be classif ied as pathogenic for autosomal recessive hearing loss based on the predicted im pact of the variant.
Invitae RCV001382464 SCV001581238 pathogenic not provided 2020-04-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Pro175Glyfs*31). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the GJB2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 228350). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). 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.

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