ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.478G>A (p.Gly160Ser) (rs34988750)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Clinical Services Laboratory,Illumina RCV000359564 SCV000382998 likely benign Deafness, autosomal dominant 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 Clinical Services Laboratory,Illumina RCV000329133 SCV000383000 likely benign Hystrix-like ichthyosis with deafness 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 Clinical Services Laboratory,Illumina RCV000674006 SCV000383001 likely benign Deafness, autosomal recessive 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 RCV000037858 SCV000603823 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000674006 SCV000799275 uncertain significance Deafness, autosomal recessive 1A 2018-04-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037858 SCV001338407 likely benign not specified 2020-02-07 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 0.0006 in 290594 control chromosomes (gnomAD and publication data), with the highest frequency observed in the African or African-American subpopulation (0.0022) in the gnomAD database. This 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587337 SCV001371289 likely benign not provided 2020-06-01 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257159 SCV001433677 likely benign Nonsyndromic hearing loss and deafness 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)

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