Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001004771 | SCV001164251 | uncertain significance | Nonsyndromic genetic hearing loss | 2024-01-17 | reviewed by expert panel | curation | The c.339T>G variant in GJB2 is a missense variant predicted to cause substitution of serine by arginine at amino acid 113. The highest population minor allele frequency in gnomAD v4.0.0 is 0.02% (7/26136 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL provides a score of 0.553 which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function (PP3 and BP4 are not met). An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in several probands with hearing loss, including 3 individuals with a second pathogenic variant without phase confirmation (1.5 points, PM3, PMID: 15365987, 11439000, 9529365, 16380907, 24078562). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PS3_Moderate, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024). |
| Fulgent Genetics, |
RCV005007886 | SCV005634665 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A | 2024-02-03 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001004771 | SCV003800953 | likely pathogenic | Nonsyndromic genetic hearing loss | 2023-01-17 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.339T>G (p.Ser113Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250234 control chromosomes. c.339T>G has been reported in the literature as a compound heterozygous genotype in at-least two individuals reportedly affected with features of non syndromic hearing loss (NSHL) and as a non-informative genotype (second allele not specified) in many non syndromic hearing loss cohorts (example, Kelley_1998, McGuirt_2002, Gardner_2006, Snoeckx_2005, Wang_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Bruzzone_2003). The most pronounced variant effect results in loss of junctional conductance due to inability to form homotypic junctional channels. Two clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3 including the expert panel; Likely pathogenic, n=2) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001379118 | SCV001576857 | likely pathogenic | not provided | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 113 of the GJB2 protein (p.Ser113Arg). This variant is present in population databases (rs80338946, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 9529365, 12408072, 24078562). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21385). 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 not expected to disrupt GJB2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Illumina Laboratory Services, |
RCV000020568 | SCV000383017 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2017-04-27 | criteria provided, single submitter | clinical testing | The GJB2 c.339T>G (p.Ser113Arg) missense variant has been reported in at least three studies in which it is found a total of four patients with an autosomal recessive form of nonsyndromic hearing loss, including in two in a compound heterozygous state and two in a heterozygous state where the zygosity of the variant is unknown (Kelly et al. 1998; Azaiez et al. 2004; Wang et al. 2013). The p.Ser113Arg variant was absent from 96 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies in Xenopus oocytes demonstrated that the variant resulted in only background levels of junctional conductance and did not induce the formation of homotypic junctional channels (Bruzzone et al. 2003). Structural modelling experiments showed that the variant is located at a conserved site (Fan et al. 2012). Based on the available evidence the p.Ser113Arg variant is classified as likely pathogenic for an autosomal recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Counsyl | RCV000020568 | SCV000800725 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 1A | 2017-06-13 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |
| Gene |
RCV000020568 | SCV000041044 | not provided | Autosomal recessive nonsyndromic hearing loss 1A | no classification provided | literature only |