Submissions for variant NM_004004.6(GJB2):c.478G>A (p.Gly160Ser)

gnomAD frequency: 0.00107  dbSNP: rs34988750

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037858	SCV000061520	benign	not specified	2010-12-17	criteria provided, single submitter	clinical testing	Gly160Ser in exon 2 of GJB2: This variant has been identified at a frequency of 0.1-0.5% in several studies of individuals with hearing loss (Janecke 2002, Bati ssoco 2008, Gasmelseed 2004, Ross 2007). However, in none of these individuals w as a second GJB2 variant identified. In addition, this variant has been identifi ed in 3/140 (2%) controls (Scott 1998, rs34988750). In summary, the Gly160Ser va riant is not expected to have clinical or pathological significance due to its o ccurrence at a lower frequency in cases compared to controls.
Eurofins Ntd Llc (ga)	RCV000037858	SCV000112275	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000037858	SCV000193177	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000359564	SCV000382998	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000329133	SCV000383000	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	RCV000674006	SCV000383001	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000501921	SCV000590938	uncertain significance	Nonsyndromic Deafness	2017-05-19	criteria provided, single submitter	clinical testing	Reported in gene specific databases (davinci.crg.es/deafness/index.php), ClinVar, and the scientific literature as benign. The evidence for this classification is unclear/not provided, but at least in some cases appears to be due to a reported control population allele frequency of 2% (Scott et al., 1998 PMID: 9600457). This variant is reported in population databases at frequencies of up to 0.22% (gnomAD, ExAC). In silico analyses predict an impact on the protein.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587337	SCV000603823	uncertain significance	not provided	2019-09-16	criteria provided, single submitter	clinical testing	The GJB2 c.478G>A; p.Gly160Ser variant (rs34988750) is reported heterozygously in several individuals with hearing loss who also carry one copy of a pathogenic GJB2 variant (Snoeckx 2005), but phase was not reported; however, p.Gly160Ser has also been reported in cis to a pathogenic GJB2 variant in several individuals (Zheng 2015). The p.Gly160Ser variant is found in the African population with an overall allele frequency of 0.22% (55/24922 alleles) in the Genome Aggregation Database and it is reported in ClinVar (Variation ID: 44755). The glycine at codon 160 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical and functional data, the significance of the p.Gly160Ser variant is uncertain at this time. References: Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Zheng J et al. GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. PLoS One. 2015 Jun 4;10(6):e0128691.
Counsyl	RCV000674006	SCV000799275	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2018-04-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037858	SCV001338407	likely benign	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.478G>A (p.Gly160Ser) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 1622152 control chromosomes including one homozygote, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database (v4.0.0). TThis frequency is about 85-fold higher than the estimated maximum for a pathogenic variant in GJB2 causing Autosomal Dominant Non-Syndromic Hearing Loss (NSHL) (0.0022 vs. 2.5E-05), that rules out the dominant inheritance mode for the variant. However, this frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive NSHL (0.0022 vs. 0.025), allowing no conclusion about variant significance for the recessive mode of inheritance. Additional evidence supporting the benign nature of this variant comes from a study which identified the variant in 7/7401 North American hearing loss patients (Putcha 2007). This represents a lower allele frequency (0.00047) in the North American hearing loss population, than either the highest observed allele frequency (0.0022) or the overall frequency for diverse ethnicities (0.0006) of the variant in the control cohort (in gnomAD). The variant, c.478G>A, has been reported in the literature in several individuals affected with Non-Syndromic Hearing Loss, however in most of these cases there was no second allele identified, and in some cases the variant was also mentioned to be present in heterozygosity in unaffected family member (e.g. Wu 2002, Janecke 2002, Gasmelseed 2004, Azaiez 2004, Cheng 2005, Tang 2006, Primignani 2009, Ji 2011, Koohiyan_2019, Ozylmaz_2019, Abtahi_2020); therefore these reports do not indicate a pathogenic role for the variant. Though the variant was reported to be found in homozygosity in one patient from an inbred family, no further information (i.e. co-segregation or co-occurrence data) was provided (Khalifa Alkowari 2012). In a few cases the variant was found in compound heterozygosity with a (potentially) pathogenic allele in patients; however, the phase of the variants was not confirmed by parental testing (Snoeckx 2005, Zhang 2011, Yu_2020). Moreover, the variant was also found in a compound heterozygote (V37I/G160S) with normal hearing (Roux 2004), arguing against its pathogenicity. At least two NSHL patients, homozygous for the common disease variant c.235delC, were reported to also carry the variant of interest, indicating the variant to be in the benign spectrum (Jiang 2014, Zheng 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15070423, 17041943, 15365987, 16380907, 14722929, 17426645, 12172394, 12189487, 22695344, 16222667, 9600457, 19371219, 17666888, 19043807, 22103400, 21162657, 19235794, 21366436, 19125024, 31992338, 15832357, 26043044, 24737404, 30245029, 30466042, 31569309, 31620696). ClinVar contains an entry for this variant (Variation ID: 44755). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000587337	SCV001371289	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001257159	SCV001433677	likely benign	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: the filter allele frequency of c.478G>A, p.(Gly160Ser) is 0,17% (55/24922 African alleles with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the BS1_Supporting criteria. Computational analysis predicted a damage impact of the mutation to the protein (REVELscore:0.767) meeting PP3 rule. The p.(Gly160Ser) change has been identified in heterozygous state in several hearing loss individuals among different ethnic groups (PMID: 24158611, 21162657, 24529908, 19371219, 19125024, 17660464, 16222667, 15070423). This variant has been found in two Austrian familial cases which have been tested only for GJB2 gene: the first case with both parents and child affected in which the proband and her father carried the variant in heterozygous state. The second case is composed of three affected family members: mother and her two daughters. The mother carried p.(Gly160Ser) and her two daughters were not available for the study (PMID: 12189487). Hence, the evidence provided was not enough to apply PP1 rule and was not counted. Besides, this variant has been found in cis with a known pathogenic variant in two unrelated patients (PMID: 22103400) meeting BP2 criteria. Finally, p.(Gly160Ser) change was found with p.Val37Ile and c.35delG in two patients but phase unknown applying to PM3 rule. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss (BS1_Supporting, PP3, BP2 and PM3)
Baylor Genetics	RCV000674006	SCV001524671	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2019-09-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000587337	SCV001621092	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000359564	SCV001786897	uncertain significance	Autosomal dominant nonsyndromic hearing loss 3A	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000674006	SCV001786898	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000329133	SCV001786899	uncertain significance	Ichthyosis, hystrix-like, with hearing loss	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001563854	SCV001786900	uncertain significance	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000587337	SCV001824163	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Observed several times with another pathogenic variant (phase unknown) and once in the homozygous state in patients with hearing loss in published literature (Roux et al., 2004; Snoeckx et al., 2005; Khalifa et al., 2012).; Observed in the heterozygous state with no other pathogenic GJB2 variant in many patients with hearing loss in published literature (Janecke et al., 2002; Gasmelseed et al., 2004; Tang et al., 2006; Batissoco et al., 2009); Variant does not have significant effects on gap junction communication in vitro (Hoang et al., 2009) and has been considered a benign polymorphism (Kenneson et al., 2002; Han et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12172392, 27153395, 16222667, 17660464, 22567861, 17426645, 9600457, 25388846, 25266519, 19043807, 17041943, 12172394, 15365987, 14722929, 19125024, 26043044, 19887791, 24529908, 30245029, 22103400, 16380907, 11313763, 21162657, 33096615, 31992338, 31620696, 31569309, 34338889, 27785406, 12189487, 15070423, 36579563, 19230829)
Athena Diagnostics Inc	RCV000587337	SCV002770771	uncertain significance	not provided	2021-10-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000587337	SCV004226400	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	BS1_supporting, PP3
PreventionGenetics, part of Exact Sciences	RCV003904924	SCV004727542	likely benign	GJB2-related condition	2021-03-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).