Submissions for variant NM_004004.6(GJB2):c.313_326del (p.Lys105fs)

dbSNP: rs111033253

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211774	SCV000061498	pathogenic	Rare genetic deafness	2017-05-04	criteria provided, single submitter	clinical testing	The p.Lys105fs variant in GJB2 is a well-known pathogenic variant and has been i dentified in many individuals with hearing loss who were homozygous or compound heterozygous with another pathogenic variant in GJB2 (Marlin 2005). It has been reported in 27/126134 European chromosomes and 10/20780 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/; dbSNP rs1 99976861). This frequency in the general population is consistent with the carri er frequency for autosomal recessive hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 105 and leads to a premature termination codon 5 amino acids downstream . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive hearing loss based on the predicted impact to the protein and m ultiple previously reported affected compound heterozygotes. ACMG/AMP Criteria a pplied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146016	SCV000193167	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000080370	SCV000329860	pathogenic	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22975760, 30094485, 10218527, 27224056, 25999548, 22567152, 29701678, 30168495, 30344259, 9529365, 29625052, 31980526, 31160754, 33096615, 31589614, 32067424, 26896187)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000146016	SCV000492741	pathogenic	Hearing impairment	2015-01-13	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000037836	SCV000599744	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000080370	SCV000603830	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	The GJB2 c.313_326del; p.Lys105GlyfsTer5 variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans to other pathogenic variants (Dalamon 2013, Denoyelle 1999, Kupa 2002, Mikstiene 2016). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 44737) and it is found in the general population with an overall allele frequency of 0.01% (38/281690 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 14 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.313_326del variant is considered to be pathogenic. References: Dalamon V et al. Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. Mol Biol Rep. 2013 Dec;40(12):6945-55. PMID: 24158611. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 Apr 17;353(9161):1298-303. PMID: 10218527. Kupka S et al. Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. Hum Mutat. 2002 Jul;20(1):77-8. PMID: 12112666. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 Feb 19;17:45. PMID: 26896187.
Athena Diagnostics	RCV000080370	SCV000613512	pathogenic	not provided	2020-10-20	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 (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037836	SCV000698245	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-11-18	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs) variant (alternatively also known as 313del14, 313-326del14, or 312del14) results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate gap junction protein, cysteine-rich domain and connexin, N-terminal domain (InterPro).Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln124X, p.Gln164X, c.647_650delGAGA, etc.). This variant was found in 12/121692 control chromosomes at a frequency of 0.0000986, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is recurrently reported in patients with autosomal recessive NSHL and is reported to have hearing loss less severe than the c.35delG homozygotes (Kupka_2002, Wu_2002, Cryns_2004, Marlin_2005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000080370	SCV000700403	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000037836	SCV000914614	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-08-15	criteria provided, single submitter	clinical testing	The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105GlyfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys105GlyfsTer5 variant has been identified in a total of 59 individuals with autosomal recessive nonsyndromic hearing loss including 18 homozygotes and 41 compound heterozygotes (Denoyelle et al. 1999; Marlin et al. 2005; Bazazzadegan et al 2012; Mikstiene et al. 2016). Thirty-seven of the compound heterozygotes carry c.35delG, a well known pathogenic variant, on the second allele. The p.Lys105GlyfsTer5 variant was found in a heterozygous state in two control individuals and is reported at a frequency of 0.00032 in the South Asian population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Lys105GlyfsTer5 variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV001004389	SCV001163361	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000037836	SCV001194006	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-26	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 22567152. Classification of NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000080370	SCV001227363	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys105Glyfs*5) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033253, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 22567152, 26896187, 27224056). ClinVar contains an entry for this variant (Variation ID: 44737). This variant disrupts the p.Pro173, p.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 10982180, 15855033, 25708704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000080370	SCV001245650	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	GJB2: PM3:Very Strong, PVS1, PM2
INGEBI, INGEBI / CONICET	RCV001257561	SCV001434015	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.313_326del (p.Lys105fs*5) variant in the GJB2 gene is 0,015% (9/30614 South Asian alleles with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria. The c.313_326del variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in trans with at least 4 pathogenic variants in different hearing loss patients (PMID: 10218527, 10982180, 11551103, 24158611, 27224056) applying to PM3_VeryStrong. This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PVS1, PM3_VeryStrong.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000080370	SCV001449875	pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV000146016	SCV001571779	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Moderate, PM3_Moderate
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000037836	SCV001870363	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-04-12	criteria provided, single submitter	research	ACMG codes:PVS1, PM2, PP5
Revvity Omics, Revvity	RCV000080370	SCV002024256	pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000037836	SCV002579735	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-12-09	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000080370	SCV002818209	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000080370	SCV004225744	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	PM2_supporting, PM3_very_strong, PVS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV000037836	SCV005368213	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-07-23	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_VSTR
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000037836	SCV005398420	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (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) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is a commonly reported pathogenic variant (ClinVar, Deafness Variation database), and has been reported in the literature in many individuals with hearing loss (PMIDs: 26896187, 27224056, 36579563). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000037836	SCV000038814	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2004-08-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678878	SCV000805071	pathogenic	Hearing loss	2014-11-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000037836	SCV001453338	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000037836	SCV001984287	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-01-25	flagged submission	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV000037836	SCV004231803	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-06-24	no assertion criteria provided	clinical testing	The p.Lys105Glyfs*5 variant in the GJB2 gene is a well reported cause of nonsyndromic hearing loss. This variant was determined to be in trans with other pathogenic variants (p.Gly12Valfs*2, p.Met34Thr), consistent with autosomal recessive inheritance (Marlin et al., 2005; Mikstiene et al., 2016). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Lys105Glyfs*5 variant has also been identified in 9/30,614 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant results in a 14 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 5 amino acids downstream. Loss of function is an established mechanism of disease for the GJB2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys105Glyfs*5 variant as pathogenic for autosomal recessive nonsyndromic hearing loss based on the information above. [ACMG evidence codes used: PVS1; PM3_verystrong; PM2_supporting]