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

Total submissions: 7

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
Integrated Genetics/Laboratory Corporation of America	RCV000169169	SCV000919430	pathogenic	Deafness, autosomal recessive 1A	2018-09-11	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.35dupG (p.Val13CysfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 244704 control chromosomes (gnomAD and publications). The variant, c.35dupG, has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (Dai_2009, Bazazzadegan_2012, Hjelm_2010, Rabionet_2000, DAndrea_2002, Godbole_2010, Usami_2012, Banjara_2015). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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