ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.11G>A (p.Gly4Asp) (rs111033222)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037814 SCV000061476 benign not specified 2011-01-28 criteria provided, single submitter clinical testing Gly4Asp in exon 2 of GJB2: This variant is not expected to have clinical signifi cance due to an equal occurrence in probands (0.52% (25/4779)) and controls (0.3 5% (23/665)) (Yaun 2010, Dia 2009, Han 2008, Lee 2008, Tang 2006, Snoeckx 2005, Roux 2004, Hwa 2003) with a 10% (20/200) frequency in the Indonesian population (Snoeckx 2005). In addition, this variant has been identified in one individual in cis with another pathogenic GJB2 variant (Yaun 2010).
Genetic Services Laboratory,University of Chicago RCV000037814 SCV000193157 uncertain significance not specified 2016-02-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037814 SCV000227313 likely benign not specified 2015-01-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000321209 SCV000383046 likely benign Deafness, autosomal recessive 1A 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000290549 SCV000383048 likely benign Hystrix-like ichthyosis with deafness 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000345561 SCV000383049 likely benign Deafness, autosomal dominant 3a 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000037814 SCV000698227 likely benign not specified 2018-02-07 criteria provided, single submitter clinical testing Variant summary: GJB2 c.11G>A (p.Gly4Asp) 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 0.00055 in 288568 control chromosomes, predominantly observed within the East Asian subpopulation at a frequency of 0.006 in the gnomAD database and in publication data (Hwa 2003, Roux 2004, Han 2008, Chiong 2013, Snoeckx 2005, Zainal 2012). Though this frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.006 vs 0.025), at least 2 homozygous occurrence were observed among healthy controls (gnomAD and Snoeckx 2005), suggesting against the pathogenic role for the variant. Though the c.11G>A variant has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, who were compound heterozygous for this variant and another pathogenic variant, viz. p.V37I (Al-Qahtani 2010, Dai 2009, Lipan 2011) and c.235delC (Xin 2013), in one patient this variant also co-occurred in cis with a pathogenic variant, IVS1+1G>A, suggesting against pathogenicity (Yuan 2010). In addition, in two studies (carried out in East Asian subpopulations), the variant was observed with a similar (or even larger) frequency in healthy controls than in patients (Snoeckx 2005, Zainal 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as likely benign and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV000037814 SCV000728497 likely benign not specified 2018-02-12 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756205 SCV000883946 likely benign not provided 2018-03-28 criteria provided, single submitter clinical testing The GJB2 c.11G>A, p.Gly4Asp variant (rs111033222) has been reported in individuals with non-syndromic hearing impairment (Dai 2009, Hwa 2003, Tang 2006, Yao 2013). However, it has also been reported in the general population at similar frequencies (Roux 2004, Snoeckx 2005, Tang 2006, Zainal 2012), and found in-cis with a pathogenic variant (Yuan 2010). The variant is listed in ClinVar (Variation ID: 44724), and observed in the Genome Aggregation Database at a frequency of 0.046% (126/275028 alleles, including 1 homozygote). The glycine at residue 4 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that the variant has no impact on the protein. Based on the above information, the variant is considered likely benign. References: Dai P et al. GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med. 2009; 7:26. Hwa H et al. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med. 2003; 5(3):161-5. Roux A et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004; 5:5. Snoeckx R et al. GJB2 (connexin 26) mutations are not a major cause of hearing loss in the Indonesian population. Am J Med Genet A. 2005; 135(2):126-9. Tang H et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22):2401-15. Yao G et al. Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. Acta Otolaryngol. 2013; 133(8):833-41. Yuan Y et al. Prevalence of the GJB2 IVS1+1G >A mutation in Chinese hearing loss patients with monoallelic pathogenic mutation in the coding region of GJB2. J Transl Med. 2010;8:127. Zainal S et al. Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2012; 76(8):1175-9.
Invitae RCV000756205 SCV001032929 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000756205 SCV001143659 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing

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