ClinVar Miner

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

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Total submissions: 7
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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 2020-02-11 criteria provided, single submitter clinical testing The c.-22-6T>C variant in GJB2 is classified as likely benign because it has been identified in 0.09% (114/126646) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), a T>C change at this nucleotide position does not diverge from the splice consensus sequence making it unlikely to impact splicing, and computational splice prediction tools do not predict an impact on splicing. While it has been previously reported in 6 individuals with hearing loss, these individuals were heterozygous and a second GJB2 or DFNB1 pathogenic variant was not identified (Tang 2006, Stanghellini 2014, Figueroa-Ildefonso 2019, LMM Data). This variant has also been reported in ClinVar (Variation ID 228700). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP7.
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
Invitae RCV000590691 SCV001090283 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109961 SCV001267345 benign Hystrix-like ichthyosis with deafness 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001109962 SCV001267346 uncertain significance Deafness, autosomal dominant 3a 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001109963 SCV001267347 uncertain significance Deafness, autosomal recessive 1A 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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