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

Total submissions: 10

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	RCV000296493	SCV000383051	likely benign	Mutilating keratoderma	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000351365	SCV000383052	likely benign	Hystrix-like ichthyosis with deafness	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000391696	SCV000383053	likely benign	Keratitis ichthyosis and deafness syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000311687	SCV000383054	likely benign	Nonsyndromic Hearing Loss, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000336963	SCV000383055	likely benign	Nonsyndromic Hearing Loss, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
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