ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.229T>C (p.Trp77Arg) (rs104894397)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211765 SCV000061487 pathogenic Rare genetic deafness 2010-09-27 criteria provided, single submitter clinical testing The Trp77Arg variant has been reported in many individuals with hearing loss and was absent from many controls (Carrasquillo 1997, Dalamon 2005, Marlin 2005, Pr asad 2000, Rabionet 2000, Shahin 2002, Snoeckx 2005). It was also found to segre gate with hearing loss in one large kindred (Carrasquillo 1997). In summary, thi s variant meets our criteria to be classified as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000080368 SCV000227324 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing
GeneDx RCV000080368 SCV000322428 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing The W77R variant in the GJB2 gene has been reported previously in association with autosomal recessive hearing loss when present in the homozygous state or when in trans with another pathogenic variant (Carrasquillo et al., 1997; Cryns et al., 2004). This variant is observed in 7/33,582 alleles (0.021%) from individuals of Latino background in the gnomAD dataset (Lek et al., 2016). Functional studies demonstrate that the W77R variant did not form homotypic junctional channels, had impaired intercellular coupling, was inefficiently targeted to the plasma membrane, and was retained in intracellular stores (Martin et al., 1999; Bruzzone et al., 2003) The W77R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Missense variants in nearby residues (R75W, R75Q, L76P, A78T, A78S, L79V, L79P) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret W77R as a pathogenic variant.
Counsyl RCV000412297 SCV000487394 pathogenic Deafness, autosomal dominant 3a 2016-03-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018526 SCV000917453 pathogenic Deafness, autosomal recessive 1A 2018-11-21 criteria provided, single submitter clinical testing Variant summary: GJB2 c.229T>C (p.Trp77Arg) results in a non-conservative amino acid change located in the connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 246400 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.1e-05 vs 0.025), allowing no conclusion about variant significance. c.229T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (Alvarez 2005, Carrasquillo 1997, Snoeckx 2005), and the variant was also found to segregate with the disease in one of these reported families (Carrasquillo 1997). These data indicate that the variant is very likely to be associated with disease. Functional studies have shown to have >99% reduction in junctional conductance in comparison to wild-type (Bruzzone_2003). Three 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000080368 SCV000958603 pathogenic not provided 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 77 of the GJB2 protein (p.Trp77Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs104894397, ExAC 0.001%). This variant has been observed in individual(s) with non-syndromic hearing loss (PMID: 19371219, 16467727, 16545002). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17003). This variant has been reported to affect GJB2 protein function (PMID: 10556284, 12064630, 12505163). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004394 SCV001163366 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000018526 SCV001194211 pathogenic Deafness, autosomal recessive 1A 2019-12-09 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.229T>C(W77R) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 15967879, 22785241, 16380907, 10556284 and 12505163. Classification of NM_004004.5(GJB2):c.229T>C(W77R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000018526 SCV001244781 pathogenic Deafness, autosomal recessive 1A 2017-08-30 criteria provided, single submitter clinical testing A homozygous missense variant was identified, NM_004004.5(GJB2):c.229T>C in exon 2 of the GJB2 gene. This substitution is predicted to create a major change from a tryptophan to an arginine at position 77, NP_003995.2(GJB2):p.(Trp77Arg). The tryptophan at this position has very high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing. It is situated in the second transmembrane domain and functional studies have shown that it causes loss of channel activity. (Martin, PE. et al. (1999), Bruzzone, R. et al. (2002)). This variant is present in the gnomAD population database at a frequency of 0.0041% (10 in 246208, 0 homozygotes). It is one of the more frequent GJB2 variants and has been previously reported in patients with autosomal recessive deafness (Cryns, K. et al. (2004), Snoeckx, RL. et al. (2005), ClinVar). Based on current information, this variant has been classified as PATHOGENIC.
INGEBI, INGEBI / CONICET RCV001257039 SCV001433544 pathogenic Nonsyndromic hearing loss and deafness 2020-08-21 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.229T>C, p.Trp77Arg variant has a filtering allele frequency of 0,00949% (7/34590 of Latino alleles with 95% CI) from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_supporting criteria. This variant has been identified in trans with different pathogenic variants in at least four patients: (PMID: 9328482, 11935342, 15964725, 16088916, 16380907, 22785241, PMID:16467727, 16545002, 19371219) applying to PM3_VeryStrong. Computational evidence showed a damage impact of the mutation to the protein (REVEL: 0.934) meeting PP3 rule. Functional studies in HeLa cells and Xenopus laevis oocytes demonstrated a deleterious effect of the mutant without dominant effect to Human CX26 by dye transfer and junctional conductance measurements assays. In both cases the levels of dye transfer and conductance did not exceed background levels (PMID: 10556284, PMID: 12064630, PMID: 12505163) applying to PS3_Moderate rule. Therefore, the c.229T>C variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2_Supporting, PM3_VeryStrong, PP3 and PS3_Moderate).
OMIM RCV000018526 SCV000038808 pathogenic Deafness, autosomal recessive 1A 1997-11-01 no assertion criteria provided literature only
Natera, Inc. RCV000018526 SCV001453346 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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