Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000037832 | SCV000061494 | likely pathogenic | Rare genetic deafness | 2017-06-06 | criteria provided, single submitter | clinical testing | The p.Met93Ile variant in GJB2 has been reported in at least 8 individuals with hearing loss including four compound heterozygotes with pathogenic variants in t rans (Wu 2002, Cryns 2004, Najmabadi 2005, Snoeckx 2005, Putcha 2007, Naghavi 20 08, Rodriguez-Paris 2010, Tsukada 2010, LMM data). (Wu 2002, Cryns 2004, Tsukada 2010). The hearing loss described in these four individuals ranged from mild t o moderately-severe (Wu 2002, Cryns 2004, Tsukada 2010, LMM data). This variant has also been identified in 4/126570 European chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516871). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for nonsyndromic hear ing loss. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Met93Ile variant is li kely pathogenic based on compound heterozygosity in multiple affected individual s. |
| Gene |
RCV000523752 | SCV000617688 | likely pathogenic | not provided | 2021-02-05 | criteria provided, single submitter | clinical testing | 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: 18776652, 16380907, 14985372, 25616557, 17666888, 20497192, 20668687, 12172394, 25388846, 28483220, 25555641, 25447126, 22592158, 22695344, 30245029, 30708180, 24156272, 15666300) |
| ARUP Laboratories, |
RCV000523752 | SCV002048130 | likely pathogenic | not provided | 2021-10-21 | criteria provided, single submitter | clinical testing | The GJB2 c.279G>A; p.Met93Ile variant (rs397516871) is reported in the literature in multiple individuals affected with hearing loss often found with a second pathogenic variant (Cryns 2004, Naghavi 2008, Najmabadi 2005, Putcha 2007, Wu 2002). This variant is also reported in ClinVar (Variation ID: 44733). This variant is found in the non-Finnish European population with an allele frequency of 0.003% (3/113608 alleles) in the Genome Aggregation Database. The methionine at codon 93 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.874). Based on available information, this variant is considered to be likely pathogenic. References: Cryns K et al. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004 Mar;41(3):147-54. PMID: 14985372. Naghavi A et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. PMID: 18776652. Najmabadi H et al. GJB2 mutations: passage through Iran. Am J Med Genet A. 2005 Mar 1;133A(2):132-7. PMID: 15666300. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. PMID: 17666888. Wu BL et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002 Jul-Aug;4(4):279-88. PMID: 12172394. |
| Invitae | RCV000523752 | SCV002274257 | pathogenic | not provided | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 93 of the GJB2 protein (p.Met93Ile). This variant is present in population databases (rs397516871, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 12172394, 14985372). ClinVar contains an entry for this variant (Variation ID: 44733). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 22592158). This variant disrupts the p.Met93 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000675160 | SCV002511672 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2022-04-05 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.279G>A (p.Met93Ile) results in a 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251190 control chromosomes. c.279G>A has been reported in the literature in individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Wu_2002, Cryns_2004, Snoeckx_2005, Tsukada_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV002482993 | SCV002786112 | 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; X-linked mixed hearing loss with perilymphatic gusher | 2022-05-17 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000675160 | SCV000800777 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 1A | 2017-07-17 | no assertion criteria provided | clinical testing |