ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.1A>G (p.Met1Val) (rs111033293)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.; 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 Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168669 SCV000603820 pathogenic not specified 2016-08-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724654 SCV000700808 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762907 SCV000893317 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000724654 SCV000932188 pathogenic not provided 2018-12-26 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, ExAC 0.01%). Variants affecting the initiator codon of GJB2 have been observed in several individuals and families affected with non-syndromic hearing loss (PMID: 9482292, 20146813, 18941476, 10218527, 17666888, 22695344, 16380907). ClinVar contains an entry for this variant (Variation ID: 44729). Experimental studies have shown that this initiator codon change has a deleterious effect on protein expression (PMID: 12189493). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000724654 SCV001795810 pathogenic not provided 2021-02-19 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: 33504652, 29625052, 29542069, 18941476, 18983339, 9710598, 10218527, 12910486, 15488970, 16532460, 23555729, 23695287, 20083784, 16380907, 16950989, 9482292, 12189493, 20146813)
Counsyl RCV000037821 SCV000220945 pathogenic Deafness, autosomal recessive 1A 2016-10-12 no assertion criteria provided clinical testing
Natera, Inc. RCV000037821 SCV001455335 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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