ClinVar Miner

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

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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 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.
Integrated Genetics/Laboratory Corporation of America RCV000590296 SCV000698259 likely benign not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.-45C>A variant is located in the 5' UTR causing an alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in the large, broad control population, gnomAD with an allele frequency of 71/30972, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0259808) for an autosomal recessive mode of inheritance. It should be noted that the gnomAD dataset has yet to be validated by the LCA VSG, therefore, this observation needs to be cautiously considered at this time. An allele-based expression analysis showed presence of the expressed GJB2 gene (Wilch_2006) indicating the variant no to have an impact on protein expression. Furthermore, 3/4 publications classify the variant as polymorphism, 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. In addition, two reputable sources (LMM and Deafness variation database) list this variant as 'likely benign'. Taken together, this variant is classified as "likely 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 RCV000590296 SCV000841709 likely benign not provided 2018-08-08 criteria provided, single submitter clinical testing

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