ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.428G>A (p.Arg143Gln) (rs104894401)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000018543 SCV000487494 likely pathogenic Deafness, autosomal recessive 1A 2016-01-28 criteria provided, single submitter clinical testing
Counsyl RCV000018542 SCV000487495 likely pathogenic Deafness, autosomal dominant 3a 2016-01-28 criteria provided, single submitter clinical testing
GeneDx RCV000484997 SCV000568706 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The c.428 G>A (p.R143Q) variant in the GJB2 gene has been reported previously in the compound heterozygous state in multiple unrelated individuals with congenital, profound, non-syndromic, sensorineural deafness; however, c.428 G>A has also been reported in the heterozygous state in both mildly affected and unaffected relatives of these individuals, indicating that this variant may exhibit autosomal dominant inheritance with incomplete penetrance, but also result in severe hearing loss when present in trans with an autosomal recessive GJB2 variant (Loffler et al., 2001; Bonyadi et al., 2009; Huang et al., 2013; Riahi et al., 2013). The c.428 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice models predict that c.428 G>A may create a cryptic splice acceptor site that could supplant the natural splice acceptor site for intron 1. However, in the absence of RNA/functional studies, the actual effect of the c.428 G>A change in this individual is unknown. If c.428 G>A does not alter splicing, it will result in the R143Q missense change. The R143Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved across species. Functional studies of the R143Q missense variant have demonstrated that this variant can participate in forming gap junctions, but the resulting channels exhibit both impaired function and permeability (Yum et al., 2010; Zhang et al., 2011). We interpret c.428 G>A (p.R143Q) as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000018543 SCV000698258 pathogenic Deafness, autosomal recessive 1A 2016-11-03 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.428G>A (p.Arg143Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 125474 control chromosomes. The variant has been reported in affected individuals in the heterozygous state, suggesting a dominant role of the variant. However, compound heterozygotes have been reported who have severe/profound hearing loss, indicating a more severe phenotype than individuals with only one variant. The variant was shown to co-segregate with disease in multiple families, with the exception of an affected indivdual not carrying the variant (Loffler_2001), and one unaffected family member in each study carrying the variant, suggestive of incomplete penetrance (Riahi_2013, Bonyadi_2009). One database classified this variant as pathogenic. In addition, p.Phe142Leu, p.Arg143Trp, p.Arg143Leu have been reported to associate with NSHL, suggesting Phe142-Arg143 is a mutation hot-spot. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000484997 SCV000703678 pathogenic not provided 2016-12-08 criteria provided, single submitter clinical testing
Baylor-Hopkins Center for Mendelian Genomics,Johns Hopkins University RCV000018542 SCV000924176 likely pathogenic Deafness, autosomal dominant 3a criteria provided, single submitter research
Invitae RCV000484997 SCV001591095 pathogenic not provided 2020-07-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 143 of the GJB2 protein (p.Arg143Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 22991996, 31379920). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17017). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg143 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15365987, 19715472, 9393973). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018542 SCV000038824 pathogenic Deafness, autosomal dominant 3a 2001-03-01 no assertion criteria provided literature only
OMIM RCV000018543 SCV000038825 pathogenic Deafness, autosomal recessive 1A 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV000018542 SCV000574687 pathogenic Deafness, autosomal dominant 3a 2016-12-22 no assertion criteria provided literature only
Natera, Inc. RCV000018543 SCV001463368 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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