Submissions for variant NM_004004.6(GJB2):c.-22-6T>C

gnomAD frequency: 0.00044  dbSNP: rs141962118

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219387	SCV000271797	likely benign	not specified	2020-02-11	criteria provided, single submitter	clinical testing	The c.-22-6T>C variant in GJB2 is classified as likely benign because it has been identified in 0.09% (114/126646) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), a T>C change at this nucleotide position does not diverge from the splice consensus sequence making it unlikely to impact splicing, and computational splice prediction tools do not predict an impact on splicing. While it has been previously reported in 6 individuals with hearing loss, these individuals were heterozygous and a second GJB2 or DFNB1 pathogenic variant was not identified (Tang 2006, Stanghellini 2014, Figueroa-Ildefonso 2019, LMM Data). This variant has also been reported in ClinVar (Variation ID 228700). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219387	SCV000698236	likely benign	not specified	2022-02-21	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.-22-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00049 in 249434 control chromosomes, predominantly at a frequency of 0.00094 within the Non-Finnish European subpopulation in the gnomAD database. Though this frequency may rule out an autosomal dominant mode of inheritance, it is not higher than the estimated maximum for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.026), allowing no conclusion about variant significance. c.-22-6T>C, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Tang_2006, Stanghellini_2014, Figueroa-Ildefonso_2019), however in none of these cases was a second GJB2 mutation in trans detected. These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus as benign/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics	RCV000590691	SCV000841701	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590691	SCV001090283	likely benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109961	SCV001267345	benign	Ichthyosis, hystrix-like, with hearing loss	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001109962	SCV001267346	uncertain significance	Autosomal dominant nonsyndromic hearing loss 3A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001109963	SCV001267347	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590691	SCV001474310	likely benign	not provided	2022-12-29	criteria provided, single submitter	clinical testing
Neurogenetic Laboratory, Second Faculty of Medicine, Charles University	RCV001109963	SCV001571590	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2021-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000590691	SCV001822703	uncertain significance	not provided	2024-08-20	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25401782, 34062854)
Revvity Omics, Revvity	RCV000590691	SCV003816812	uncertain significance	not provided	2020-05-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590691	SCV001809389	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590691	SCV001956503	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590691	SCV001974283	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532756	SCV004729408	likely benign	GJB2-related disorder	2020-04-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).