Submissions for variant NM_004004.6(GJB2):c.35dup (p.Val13fs) (rs80338939)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169169	SCV000220400	likely pathogenic	Deafness, autosomal recessive 1A	2015-02-05	criteria provided, single submitter	literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000711350	SCV000700277	pathogenic	not provided	2012-08-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 Inc	RCV000711350	SCV000841705	pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169169	SCV000919430	pathogenic	Deafness, autosomal recessive 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 Praxis fuer Humangenetik Tuebingen	RCV000711350	SCV001148928	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000711350	SCV001168043	pathogenic	not provided	2021-06-08	criteria provided, single submitter	clinical testing	Observed in other unrelated patients with autosomal recessive nonsyndromic hearing loss in the published literature (Estivill et al., 1998; Yao et al., 2013; Huang et al., 2014); 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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24503448, 23638949, 9482292, 20639189, 29754767, 31160754, 31541171, 24077912, 27535533, 31589614, 29871260)
Invitae	RCV000711350	SCV001400140	pathogenic	not provided	2020-08-20	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the GJB2 gene (p.Val13Cysfs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acids of the GJB2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with deafness in a family and it has been reported to be in combination with another GJB2 variant in unrelated individuals affected with deafness (PMID: 23638949, 11439000, 24503448, 18519481, 19366456, 20497192). This variant is also known as 35insG in the literature. 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	Deafness, autosomal recessive 1A	2019-02-26	no assertion criteria provided	case-control