ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00003  dbSNP: rs111033293
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000211762 SCV000061483 pathogenic Rare genetic deafness 2016-03-03 criteria provided, single submitter clinical testing The c.1A>G in GJB2 has been reported in at least 8 individuals with nonsyndromic hearing loss and segregated with disease in 1 family member (Estivill 1998, Tho nnissen 2002, Snoeckx 2005, Gardner 2006, Bajaj 2008). Many of these individuals were either homozygous or compound heterozygous. In addition, this variant has now been identified by our laboratory in 4 individuals with hearing loss who wer e also compound heterozygous for another pathogenic variant affecting the other copy of GJB2. This variant has been identified in 2/66508 European chromosomes i n the heterozygous state by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs111033293). It alters the start codon, and is there fore predicted to disrupt translation. An in vitro functional study provides som e evidence that that this variant might result in complete absence of protein (T honnissen 2002). In summary, this variant meets our criteria to be classified as pathogenic in an autosomal recessive manner.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000037821 SCV000599721 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724654 SCV000603820 pathogenic not provided 2021-02-22 criteria provided, single submitter clinical testing The GJB2 c.1A>G; p.Met1? variant has been described in the literature in individuals with autosomal recessive hearing loss as compound heterozygote with another GJB2 pathogenic variant or with a GJB6 pathogenic variant (Estivill 1998, Putcha 2007, Snoeckx 2005, Thonnissen 2002). This variant occurs in the initiation codon, the first methionine in the GJB2 protein, and has been shown to not produce a full-length functional protein (Thonnissen 2002). This variant is also reported in ClinVar (Variation ID: 44729). This variant is found in the general population with an overall allele frequency of 0.0036% (10/280566 alleles) in the Genome Aggregation Database. Therefore, this variant is considered pathogenic. References: Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394-8. 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. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Thönnissen E et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 Aug;111(2):190-7.
Eurofins NTD LLC (GA) RCV000724654 SCV000700808 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762907 SCV000893317 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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000724654 SCV000932188 pathogenic not provided 2021-11-20 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs111033293, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with non-syndromic deafness (PMID: 9482292, 10218527, 18941476, 20146813). ClinVar contains an entry for this variant (Variation ID: 44729). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GJB2 function (PMID: 12189493). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000724654 SCV001795810 pathogenic not provided 2022-03-31 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that c.1A>G is a null variant (Thonnissen et al., 2002); This variant is associated with the following publications: (PMID: 20146813, 29542069, 9482292, 16950989, 16380907, 20083784, 23695287, 23555729, 16532460, 15488970, 12910486, 10218527, 9710598, 18941476, 29625052, 33504652, 12189493, 18983339)
Counsyl RCV000037821 SCV000220945 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2016-10-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000037821 SCV001455335 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000724654 SCV002024268 pathogenic not provided 2021-11-10 no assertion criteria provided clinical testing

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