Submissions for variant NM_004004.6(GJB2):c.167del (p.Leu56fs)

gnomAD frequency: 0.00058  dbSNP: rs80338942

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000211757	SCV000840535	pathogenic	Nonsyndromic genetic hearing loss	2018-09-19	reviewed by expert panel	curation	The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844699	SCV000061479	pathogenic	Rare genetic deafness	2011-12-08	criteria provided, single submitter	clinical testing	The c.167delT variant in GJB2 is known to be pathogenic with many supporting pub lications. PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146010	SCV000193161	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000255988	SCV000321727	pathogenic	not provided	2019-09-05	criteria provided, single submitter	clinical testing	Most individuals heterozygous for the c.167delT variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998); Frameshift variant predicted to result in protein truncation, as the last 171 amino acids are lost and replaced with 25 incorrect amino acids (Stenson et al., 2014); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840535.3; Oza et al., 2018); Observed in 218/276720 (0.08%) alleles from individuals in large population cohorts, including 3 homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27153395, 28702509, 22785241, 17666888, 24158611, 31160754, 25262649, 21465647, 22975760, 20739944, 11668644, 9819448, 26896187, 9285800, 26990548, 16380907, 15967879, 10982182, 23891399, 10903123, 20301449, 26096904, 24529908, 19125024, 15547683, 26236732, 11935342, 11386851, 29542069, 29984802, 27018795, 29431110, 11074495, 31370293, 31827275, 31980526, 32747562, 33096615, 31589614, 32067424)
Eurofins Ntd Llc (ga)	RCV000255988	SCV000330926	pathogenic	not provided	2015-07-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346888	SCV000383032	pathogenic	GJB2-related disorder	2018-05-16	criteria provided, single submitter	clinical testing	The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a well-known variant that is common in the Ashkenazi Jewish population, where the carrier rate is as high as 7.5% (Lerer et al. 2000). Across a selection of the available literature, the p.Leu56ArgfsTer26 variant has been identified in a total of 34 patients with autosomal recessive nonsyndromic hearing loss, including in 16 in a homozygous state, in 15 in a compound heterozygous state, and in three in a heterozygous state (Zelante et al. 1997; Morell et al. 1998; Lerer et al. 2000; Batissoco et al. 2009; Bonyadi et al. 2014; Amorini et al. 2015). The p.Leu56ArgfsTer26 variant was shown to segregate with disease in at least one family. Patients with this variant show a spectrum of phenotypic manifestation from mild to profound hearing loss, even among affected family members (Morell et al. 1998). Control data is unavailable for this variant, which is reported at a frequency of 0.00145 in the European-American population of the Exome Sequencing Project (Morell et al. 1998; Lerer et al. 2000). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu56ArgfsTer26 variant is classified as pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000409300	SCV000487400	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2015-12-18	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018534	SCV000599734	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000255988	SCV000613506	pathogenic	not provided	2022-05-24	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant is the most common pathogenic variant among the Ashkenazi Jewish population (PMID: 9819448), and therefore, the observed frequency of this variant in the general population is consistent with pathogenicity (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018534	SCV000698231	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-08-25	criteria provided, single submitter	clinical testing	Variant summary: The c.167delT variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.269dupT, c.313_326del, c.647_650delGATA, etc.). This variant was found in 84/123144 control chromosomes (3 homozygotes) at a frequency of 0.0006821, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is a well-known common pathogenic variant predominantly found in Ashkenazi Jewish population. In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255988	SCV000940600	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu56Argfs*26) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 171 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338942, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9819448, 10982182, 11935342, 15967879, 16380907, 21465647, 22695344, 24158611). ClinVar contains an entry for this variant (Variation ID: 17010). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255988	SCV001160051	pathogenic	not provided	2022-12-09	criteria provided, single submitter	clinical testing	The GJB2 c.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous c.167delT variants have been reported in a number of patients with hearing loss (Kenna 2010, Snoeckx 2005). This variant is reported to ClinVar (Variation ID: 17010), and observed in the general population databases with an overall allele frequency of 0.08 percent (218/276720 alleles), including 3 homozygotes (Genome Aggregation Database). Importantly, this variant has been reported at a carrier frequency of 2.4-7.5 percent in Ashkenazi Jewish individuals (Bors 2004, Lerer 2000, Morell 1998, Sobe 1999). Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.167delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/17010/ Bors A. et al. Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med. 2004; 14(6):1105-1108. Gualandi F et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. Kenna MA et al. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch Otolaryngol Head Neck Surg 2010; 136(1):81-87. Lerer I et al. Contribution of connexin 26 mutations in non-syndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Am. J. Med. Genet. 2000; 95:53-56. Morell RJ et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 339(21):1500-1505. Snoeckx RL et al. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. Sobe T et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet. 1999; 86:499-500.
Baylor Genetics	RCV001004395	SCV001163367	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018534	SCV001193832	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-10-18	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.167delT(L56Rfs*26) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Please note that L56Rfs*26 is associated with a variable presentation, ranging from mild to profound hearing loss. Sources cited for classification include the following: PMID 24158611, 10049954, 16380907, 10596881, 11556849, 11074495, and 10982182. Classification of NM_004004.5(GJB2):c.167delT(L56Rfs*26) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018534	SCV001244780	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-07-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive non syndromic hearing loss. However dominant negative is a likely mechanism for missense variants (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants most likely to result in lost protein function are more commonly reported for recessive disease, while missense are more commonly reported for dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Two missense variants are most commonly reported with incomplete penetrance (PMID:31160754). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD v2 >=0.01 and <0.03 for a recessive condition (221 heterozygotes, 3 homozygotes). (I) 0701 - Other truncating variants downstream of the one identified in this case have very strong previous evidence for pathogenicity. Patients with these variants are generally reported with non syndromic autosomal recessive hearing loss (ClinVar, PMID: 26096904). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been reported in patients with autosomal recessive non syndromic hearing loss (ClinVar, PMID: 26096904) (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000255988	SCV001334475	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV000211757	SCV001434023	pathogenic	Nonsyndromic genetic hearing loss	2020-08-31	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS
Revvity Omics, Revvity	RCV000255988	SCV002024265	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing
3billion	RCV000018534	SCV002058402	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017010, PMID:9285800). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000804, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 24158611, 9285800, 24529908, 26096904, 17666888, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV002227040	SCV002506439	pathogenic	See cases	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP5
Mendelics	RCV000291910	SCV002516477	pathogenic	Mutilating keratoderma	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504803	SCV002804997	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	2022-02-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513103	SCV003743260	pathogenic	Inborn genetic diseases	2020-02-11	criteria provided, single submitter	clinical testing	The alteration results in a premature stop codon: _x000D_ _x000D_ The c.167delT (p.L56Rfs*26) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, results from a deletion of one nucleotide at position 167, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of GJB2, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last three-quarters of the protein. The alteration has been observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GJB2 c.167delT alteration was observed in 0.08% (227/282466) of total alleles studied, with a frequency of 1.6% (168/10326) in the Ashkenazi Jewish subpopulation, including 3 homozygotes. The alteration has been observed in affected individuals: _x000D_ _x000D_ That alteration has been observed in conjunction with a second disease-causing allele in multiple individuals with non-syndromic hearing loss (Zelante, 1997; Morell, 1998; Dzhemileva, 2010; Mikstiene, 2016). Based on the available evidence, this alteration is classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000018534	SCV003927250	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-04-28	criteria provided, single submitter	clinical testing
OMIM	RCV000018534	SCV000038816	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	1998-11-19	no assertion criteria provided	literature only
GeneReviews	RCV000018534	SCV000041040	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477920	SCV000536799	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	2016-01-25	no assertion criteria provided	research
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678869	SCV000805062	pathogenic	Hearing loss	2013-05-22	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000018534	SCV001453351	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing