Submissions for variant NM_004004.6(GJB2):c.35dup (p.Val13fs)

dbSNP: rs80338939

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169169	SCV000220400	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-02-05	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000711350	SCV000700277	pathogenic	not provided	2012-08-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000609278	SCV000710859	pathogenic	Rare genetic deafness	2016-11-30	criteria provided, single submitter	clinical testing	The p.Val13fs variant in GJB2, also reported as c.35dupG or c.35insG, has been r eported in >5 individuals with hearing loss who were compound heterozygous for a second pathogenic variant in GJB2 (Estivill 1998, Huang 2014, Snoeckx 2005, Tsu kada 2010). It has been identified in 6/250260 of the total chromosomes in the genome Aggregation Database (http://gnomad.broadinstitute.org/, dbSNP rs39812381 4). This low frequency in the general population is consistent with the carrier frequency for autosomal recessive hearing loss. This variant is predicted to ca use a frameshift, which alters the protein?s amino acid sequence beginning at po sition 13 and leads to a premature termination codon 35 amino acids downstream. In summary, this variant meets criteria to be classified as pathogenic for autos omal recessive hearing loss based on the predicted impact to the protein and mul tiple previously reported affected compound heterozygotes.
Athena Diagnostics	RCV000711350	SCV000841705	pathogenic	not provided	2023-01-10	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In multiple individuals with nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. In some published literature, this variant is referred to as c.35insG.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169169	SCV000919430	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-02-09	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.35dupG (p.Val13CysfsX35) results in a premature termination codon, predicted to cause a truncation, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 249362 control chromosomes (gnomAD). c.35dupG has been reported in the literature in several individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Rabionet_2000, D'Andrea_2002, Dai_2009, Hjelm_2010, Godbole_2010, Bazazzadegan_2012, Usami_2012, Banjara_2015, Liu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000711350	SCV001148928	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000711350	SCV001168043	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are replaced with 34 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9482292, 29754767, 31589614, 31541171, 29871260, 32645618, 31160754, 34416374, 23638949, 20639189, 24503448)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711350	SCV001400140	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val13Cysfs*35) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs398123814, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 11439000, 18519481, 19366456, 20497192, 23638949, 24503448). It has also been observed to segregate with disease in related individuals. This variant is also known as 35insG. ClinVar contains an entry for this variant (Variation ID: 94392). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000711350	SCV001448869	pathogenic	not provided	2016-11-23	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000711350	SCV001480167	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375474	SCV001572147	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Moderate, BP5_Supporting
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678861	SCV000805054	pathogenic	Hearing loss	2009-01-22	no assertion criteria provided	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000169169	SCV000902319	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
WangQJ Lab, Chinese People's Liberation Army General Hospital	RCV000169169	SCV001762422	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169169	SCV002086072	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-10-24	no assertion criteria provided	clinical testing