ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.-22-6T>C (rs141962118)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000219387 SCV000271797 likely benign not specified 2018-08-01 criteria provided, single submitter clinical testing The c.-22-6T>C variant in GJB2 is classified as likely benign because it has bee n identified in 0.09% (113/124252) of European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/), a T>C change at this position does not diverge from the splice consensus sequence, and computational tools do not suggest an impact to splicing. Although it has been reported in thr ee individuals with hearing loss, none of these individuals had a second GJB2 va riant identified (Tang 2006, Stanghellini 2014, LMM Data). ACMG/AMP Criteria app lied: BS1_Supporting, BP4.
Integrated Genetics/Laboratory Corporation of America RCV000219387 SCV000698236 uncertain significance not specified 2019-08-27 criteria provided, single submitter clinical testing Variant summary: GJB2 c.-22-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00049 in 249434 control chromosomes, predominantly at a frequency of 0.00094 within the Non-Finnish European subpopulation in the gnomAD database. Though this frequency rules out an autosomal dominant mode of inheritance, it is not higher than the expected maximum for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.026), allowing no conclusion about variant significance. The variant, c.-22-6T>C, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Tang_2006, Stanghellini_2014, Figueroa-Ildefonso_2019), however in none of these cases was a second GJB2 mutation in trans detected. These reports therefore do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics Inc RCV000590691 SCV000841701 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing

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