ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.385G>A (p.Glu129Lys) (rs397516875)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037849 SCV000061511 uncertain significance not specified 2013-02-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Glu129Lys varia nt in GJB2 has been reported in 5 individuals with sensorineural hearing loss (K enna 2001, Dalamon 2005, Najmabadi 2005, Primignani 2009, Putcha 2007). Only 1 o f these individuals had a variant on the other allele, though the one other vari ant (Ala40Gly) is also of unknown significance. In another family, both the fath er and proband had unilateral high frequency sensorineural hearing loss raising the possibility of a dominant pattern of inheritance (Kenna 2001) though this is not consistent with the other 4 cases in the literature. This variant has not b een identified in large and broad ethnically-matched populations by NHLBI Exome Sequencing Project ( Computational analyses (b iochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional data is needed to determine the clinical significance of this variant; however, given th e absence of clear disease-causing variants on the second allele of any of the r eported case, we would lean towards a more likely benign interpretation.
Eurofins NTD, LLC RCV000730888 SCV000858655 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001089545 SCV001244784 uncertain significance Deafness, autosomal recessive 1A 2017-09-12 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_004004.5(GJB2):c.385G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from an glutamic acid to a lysine at position 129, NP_003995.2(GJB2):p.(Glu129Lys). The glutamic acid at this position has low conservation (100 vertebrates, UCSC). In silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). This variant has been previously observed in other deafness cases (Kenna, MA. et al. (2001), Dalamon, V. et al. (2005), Wu, B-L. et al. (2002) and Toth, T. et al. (2007)) and reported as PATHOGENIC in the Deafness Variation Database but evidence for its pathogenicity is conflicting and it is designated as a variant of uncertain significance in ClinVar. This variant is present in the gnomAD population database at a frequency of 0.0057% (14/245256, 0 hom). It is not situated in a known functional domain. The homozygous presence of the NM_004004.5(GJB2):c.101T>C variant in the same patient suggests that this variant (NM_004004.5(GJB2):c.385G>A) is in cis with one of the alleles. Based on current information, this variant has been classified as a VARIANT of UNKNOWN SIGNIFICANCE (VUS).
INGEBI, INGEBI / CONICET RCV001257047 SCV001433598 uncertain significance 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 filtering allele frequency of c.385G>A, p.(Glu129Lys) variant in GJB2 gene is 0,00385% (4/35432 Latino alleles with 95%CI) from Genome Aggregation Database (; calculated by using inverse allele frequency at which meets the criteria to apply to PM2 rule. Computational evidence was not enough to neither apply to PP3 nor BP4 since REVEL score was 0.560. The p.(Glu129Lys) change has been identified in heterozygous state in six patients (PMID: 15666300, 17666888, 15964725, 11556849). In addition, it was reported (PMID: 11556849) that this variant could segregate in a dominant mode (data not shown) in patient with unilateral high frequency hearing loss and his affected father. However, since segregation analysis was not performed, this information was not counted. On the other hand, p.(Glu129Lys) has been identified in trans with a presumed pathogenic variant (p.Ala40Gly) (PMID: 19371219) meeting PM3 criteria. In summary, the clinical significance of this variant is currently uncertain (PM2, PM3).
GeneDx RCV000730888 SCV001802615 uncertain significance not provided 2019-10-22 criteria provided, single submitter clinical testing Observed multiple times in individuals with hearing loss; however, it is most commonly observed as heterozygous in cases of sporadic hearing loss where no other GJB2 variant is identified (Najmabadi et al., 2005; Tth et al., 2007; Dalamn et al., 2013).; In addition, has been observed on the opposite allele (in trans) from the c.35delG pathogenic variant in an individual without hearing loss (Chinetti et al., 2011).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33096615, 30275481, 30245029, 25447126, 12925341, 12172394, 21916817, 22695344, 25012701, 17671735, 15666300, 15964725, 17666888, 19371219, 19081147, 19887791, 28483220, 24156272, 25388846, 11556849, 24158611)
Natera, Inc. RCV001089545 SCV001463370 uncertain significance Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.