ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.-45C>A (rs397516868)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037808 SCV000061470 benign not specified 2017-06-13 criteria provided, single submitter clinical testing c.-45C>A in Exon 1 of GJB2: This variant has been identified in 0.4%(58/14946) o f European chromosomes by the Genome Aggregation Database (gnomAD; http://gnoma d.broadinstitute.org; dbSNP rs397516868). Expression studies showed presence of the expressed GJB2 gene (Wilch 2006).
Illumina Clinical Services Laboratory,Illumina RCV000387998 SCV000383067 uncertain significance Hystrix-like ichthyosis with deafness 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000330001 SCV000383069 uncertain significance Deafness, autosomal dominant 3a 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000375249 SCV000383070 uncertain significance Deafness, autosomal recessive 1A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037808 SCV000698259 benign not specified 2021-08-11 criteria provided, single submitter clinical testing Variant summary: GJB2 c.-45C>A is located in the untranslated mRNA region upstream of the initiation codon. One in silico tool predicts a benign outcome for this variant. The variant allele was found at a frequency of 0.0024 in 31410 control chromosomes, predominantly at a frequency of 0.0039 within the Non-Finnish European subpopulation in the gnomAD database (genomes). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.-45C>A, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss but was also found in controls (Matos_2011). In addition, multiple publications classify the variant as polymorphism (Wilch_2006, Bliznets_2012, Beck_2014), which is supported by the evidence that the variant was observed in trans with a pathogenic allele in an unaffected individual, suggesting a lack of segregation with disease. An allele-based expression analysis showed presence of the expressed GJB2 gene (Wilch_2006) demonstrating no damaging effect of this variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=2) and benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000037808 SCV000724451 likely benign not specified 2017-10-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Athena Diagnostics Inc RCV000037808 SCV000841709 likely benign not specified 2021-02-10 criteria provided, single submitter clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000037808 SCV001955484 benign not specified no assertion criteria provided clinical testing

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