ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.-6T>A (rs148136545)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037809 SCV000061471 benign not specified 2012-05-15 criteria provided, single submitter clinical testing -6T>A in Exon 02 of GJB2: This variant is not expected to have clinical signific ance because it has been identified in 1.5% (55/3738) of African American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS; dbSNP rs148136545) and has been reported as benign based on an equal occurance in cases and controls (Tang 2006, Al-Qahtani, 2010, Shan 2 010).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000037809 SCV000331239 benign not specified 2016-05-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351365 SCV000383052 benign 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000311687 SCV000383054 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.
Illumina Clinical Services Laboratory,Illumina RCV000336963 SCV000383055 benign 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Integrated Genetics/Laboratory Corporation of America RCV000037809 SCV000698271 benign not specified 2019-01-08 criteria provided, single submitter clinical testing Variant summary: GJB2 c.-6T>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0012 in 275934 control chromosomes, predominantly at a frequency of 0.012 within the African subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 36-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 African origin. The variant, c.-6T>A, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss, but also in controls (Gasmelseed_2004, Tang_2006, Shan_2010, Bosch_2014) and is considered by multiple authors a non-pathogenic common variant. These report(s) 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 ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000586780 SCV000885511 benign not provided 2017-08-30 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000586780 SCV001143675 benign not provided 2019-02-11 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001374657 SCV001571588 benign nonsyndromic sensorineural hearing loss 2021-03-04 no assertion criteria provided clinical testing

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