ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.298del (p.His100fs)

gnomAD frequency: 0.00002  dbSNP: rs775828835
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586317 SCV000698242 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-06-07 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.298delC (p.His100Metfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.K112fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121268 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Deafness variation database lists variant with classification of pathogenic. Taken together, this variant is classified as likely pathogenic until more evidence becomes available.
GeneDx RCV001009145 SCV001168960 likely pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 127 amino acids are lost and replaced with 11 incorrect amino acids; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001009145 SCV001591357 pathogenic not provided 2023-11-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His100Metfs*12) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 127 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs775828835, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 496218). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). 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.

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