Submissions for variant NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)

gnomAD frequency: 0.00003  dbSNP: rs773528125

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169473	SCV000220917	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2014-11-25	criteria provided, single submitter	literature only
Genetic Services Laboratory, University of Chicago	RCV000169473	SCV000247476	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000498375	SCV000589636	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 56 amino acids are lost and replaced with 39 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 24737404, 12172394, 16712961, 25587757, 26004784, 27247933, 27792752, 26783197, 17444514, 25891447, 24256046, 23638949, 22335977, 22695344, 28717060, 29926981, 31160754, 29871260)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000169473	SCV000599756	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169473	SCV000698264	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.508_511dupAACG (p.Ala171Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.647_650delGATA/ p.Arg216fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 2/121034 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been reported in multiple studies, in Chinese and Koreean populations with NSHL in the compound heterozygous and homozygous state (Zhu_2015, Kim_2015, Jiang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000498375	SCV000701343	pathogenic	not provided	2016-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498375	SCV001225144	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala171Glufs*40) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs773528125, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 12172394, 25891447). This variant is also known as 511-512insAACG. ClinVar contains an entry for this variant (Variation ID: 189070). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814083	SCV001755334	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169473	SCV001810445	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492693	SCV002803888	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-01-14	criteria provided, single submitter	clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000169473	SCV003935275	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017450	SCV004848388	pathogenic	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The p.Ala171fs variant in GJB2 has been reported in several individuals with nonsyndromic hearing loss in the compound heterozygous and homozygous state (Wu 2002 PubMed: 12172394, Liu 2020 PubMed: 32645618, Yuan 2020 PubMed: 31541171). It has also been identified in 4/5196 (0.07%) of East Asian chromosomes by gnomAD (httpe://gnomad.broadinstitute.org). However, this frequncy is low enough to be consistent with a recessive allele frequency. This variant is predicted cause a frameshift, which alters the protein's amino acid sequence beginning at position171 and leads to a premature termination codon 40 amino acids downstream. Several frameshift variant downstream of this variant in GJB2 have been reported as disease causing. Loss of function of the GJB2 gene is an established disease mechanism in autosomal recessive nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PVS1, PM3_S, PM2_P.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000169473	SCV000902320	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000169473	SCV001463361	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539571	SCV004783241	pathogenic	GJB2-related disorder	2023-10-27	no assertion criteria provided	clinical testing	The GJB2 c.508_511dupAACG variant is predicted to result in a frameshift and premature protein termination (p.Ala171Glufs*40). This variant has been reported in multiple individuals with non‑syndromic hearing loss (see for example, Table 1, Wu et al. 2002. PubMed ID: 12172394; Table 4, Jiang et al. 2014. PubMed ID: 24737404; Table S3, Yuan et al. 2019. PubMed ID: 31541171). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763209-G-GCGTT). Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic.