ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.35G>T (p.Gly12Val) (rs1801002)

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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 RCV000211720 SCV000061504 likely pathogenic Rare genetic deafness 2012-05-25 criteria provided, single submitter clinical testing The Gly12Val variant in GJB2 has been reported in 4 individuals with hearing los s (Kenna 2001, D'Andrea P 2002, Kenna 2010, Rabionet 2000, Snoeckx 2005). At lea st two of these individuals were compound heterozygous. In addition, functional studies suggest that the Gly12Val variant may impact protein function (D'Andrea P 2002). In summary, this data suggests that this variant is likely pathogenic.
Genetic Services Laboratory, University of Chicago RCV000146020 SCV000193172 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000711351 SCV000227310 pathogenic not provided 2013-11-05 criteria provided, single submitter clinical testing
Counsyl RCV000020570 SCV000487479 likely pathogenic Deafness, autosomal recessive 1A 2016-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000412324 SCV000487480 likely pathogenic Deafness, autosomal dominant 3a 2016-09-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000711351 SCV000603825 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The GJB2 c.35G>T; p.Gly12Val variant (rs1801002) is a frequently reported pathogenic variant in Hispanic populations (see Purnick 2000, Putcha 2007, Rabionet 2000, Wu 2002). It has been found in a compound heterozygous state with the c.35delG variant and functional studies indicate the p.Gly12Val variant alters GJB2 protein function (D'Andrea 2012). This variant is reported in ClinVar (Variation ID: 21387) and is found in the general population with an overall allele frequency of 0.009% (21/244174 alleles) in the Genome Aggregation Database. Based on available information, we consider this variant to be pathogenic. REFERENCES D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. Purnick PE et al. Structure of the amino terminus of a gap junction protein. Arch Biochem Biophys. 2000 Sep 15;381(2):181-90. 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. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4. 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.
Integrated Genetics/Laboratory Corporation of America RCV000020570 SCV000698251 pathogenic Deafness, autosomal recessive 1A 2016-06-03 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.35G>T (p.Gly12Val) variant involves the alteration of a conserved nucleotide. Gly12 lies in an intracellular domain 1 (IC1) and is a known hot spot codon for recurrent disease-causing mutations. Multiple disease-causing variants are found on this codon: c.35delG (the most common DV), c.35dupG, G12R, G12D, and G12C. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/119884 control chromosomes at a frequency of 0.00005, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in several nonsyndromic hearing loss patients in the literature in either homozygous or compound homozygous state with other pathogenic variants which is consistent with pathogenic role in recessive module. In addition, according to an in vitro study (DAndrea_2002), Gly12Val substitution causes complete intracellular retention of the connexin and accumulates in large perinuclear vesicles. This dysfunction is accompanied by a significant decrease in its expression, suggesting that G12 is required for the maturation of connexin. Multiple laboratories via ClinVar also classify the variant as pathogenic/likely pathogenic. Considering all evidences, the variant has been classified as pathogenic.
Athena Diagnostics Inc RCV000711351 SCV000841707 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing
GeneReviews RCV000020570 SCV000041046 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.

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