Submissions for variant NM_004004.6(GJB2):c.355G>A (p.Glu119Lys)

gnomAD frequency: 0.00016  dbSNP: rs150529554

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000336897	SCV000383009	likely benign	Autosomal dominant nonsyndromic hearing loss 3A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000407574	SCV000383010	likely benign	Ichthyosis, hystrix-like, with hearing loss	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000278504	SCV000383011	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757332	SCV000885516	uncertain significance	not specified	2018-07-01	criteria provided, single submitter	clinical testing	The c.355G>A; p.Glu119Lys variant (rs150529554) was previously identified in patients with sensorineural hearing loss, but its pathogenicity could not be ascertained and an accompanying pathogenic GJB2 variant could not be identified (Jaradat 2016, Putcha 2007, Wu 2002). It is reported as likely benign in ClinVar (Variation ID: 188488) and is observed in the general population at an overall frequency of 0.009% (25/275896 alleles) in the Genome Aggregation Database. The glutamate at residue 119 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Jaradat S et al. Molecular analysis of the GJB2 gene in Iraqi patients with sensorineural non-syndromic hearing loss. J Med J. J Med J 2016;50 (3):145- 155. Putcha G et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007;9(7):413-26. Wu B et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002;4(4):279-88.
Athena Diagnostics	RCV001288924	SCV001476376	uncertain significance	not provided	2020-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001288924	SCV001771217	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	Observed as heterozygous with no other GJB2 variants in patients with hearing loss in published literature (PMID: 12172394, 15365987, 15656949); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15365987, 25087612, 15656949, 17666888, 25388846, 12172394, 27153395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288924	SCV004252195	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 119 of the GJB2 protein (p.Glu119Lys). This variant is present in population databases (rs150529554, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 15365987, 15656949, 17666888; MID: 12172394). ClinVar contains an entry for this variant (Variation ID: 188488). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000278504	SCV005400141	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 (28 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant was identified in greater than 5 unrelated individuals with hearing loss, however no second variant was identified. This variant has been classified as pathogenic in the Deafness Variation Database. (PMID:17666888, PMID:12172394, PMID:15365987, ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678880	SCV000805073	uncertain significance	Hearing loss	2017-04-18	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001175238	SCV001338804	uncertain significance	Sensorineural hearing loss disorder	2019-01-10	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001288924	SCV001809130	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001288924	SCV001953120	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001288924	SCV001978704	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000278504	SCV002086050	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-11	no assertion criteria provided	clinical testing