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

gnomAD frequency: 0.00245  dbSNP: rs397516868

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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).
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	RCV000037808	SCV000841709	likely benign	not specified	2021-02-10	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000375249	SCV005399108	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0218 - Non-coding variant without known or predicted effect. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 359 heterozygotes, 0 homozygotes). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as benign and likely benign in ClinVar, but it is regarded VUS by the Deafness database. In addition, it has been detected in a heterozygous state in patients and controls (LOVD, Deafness Database, PMIDs: 16773579, 22567369, 25214170, 22567861, 22567861). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037808	SCV001955484	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727531	SCV001975135	likely benign	not provided		no assertion criteria provided	clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000375249	SCV003935274	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	flagged submission	clinical testing