rs104894408
Variant summary
Our verdict is Likely pathogenic. The variant received 1 ACMG points: 5P and 4B. BS1PM5PP3PM3
This summary comes from the ClinGen Evidence Repository: The c.34G>T (NM_004004.6) in GJB2 is a missense variant predicted to cause the substitution of glycine by cysteine at amino acid 12 (p.Gly12Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0036 (128/35104 alleles) in the Latino/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss VCEP for autosomal recessive hearing loss variants. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one proband was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID:15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong). A different pathogenic missense variant (p.Gly12Val) (ClinVar Variation ID 21387) in the same codon of GJB2 has been classified as likely pathogenic and pathogenic for hearing loss by 7 labs who are in concordance that this variant is LP/P (PM5). The computational predictor REVEL gives a score of 0.838, and the nucleotide is heavily conserved in UCSC, which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM3_Very Strong, PM5, PP3, BS1 (ClinGen Hearing Loss VCEP specifications version 2; 10/19/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA172224/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
Publications
- Bart-Pumphrey syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
- ichthyosis, hystrix-like, with hearing lossInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- keratoderma hereditarium mutilansInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
- palmoplantar keratoderma-deafness syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
- autosomal recessive nonsyndromic hearing loss 1AInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
- hearing loss, autosomal recessiveInheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- autosomal dominant keratitis-ichthyosis-hearing loss syndromeInheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
- autosomal dominant nonsyndromic hearing loss 3AInheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- autosomal dominant nonsyndromic hearing lossInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- KID syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.34G>T | p.Gly12Cys | missense_variant | Exon 2 of 2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
| GJB2 | ENST00000382844.2 | c.34G>T | p.Gly12Cys | missense_variant | Exon 1 of 1 | 6 | ENSP00000372295.1 | |||
| ENSG00000296095 | ENST00000736390.1 | n.232-3968G>T | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes 0.0000999 AC: 15AN: 150218Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000511 AC: 126AN: 246498 AF XY: 0.000397 show subpopulations
GnomAD4 exome AF: 0.0000958 AC: 140AN: 1461790Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 62AN XY: 727202 show subpopulations
Age Distribution
GnomAD4 genome 0.0000998 AC: 15AN: 150336Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8AN XY: 73566 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:5
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Variant summary: GJB2 c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the 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 0.00051 in 247086 control chromosomes, predominantly at a frequency of 0.0036 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. However, the relatively high frequency of the variant suggests that it is unlikely to be associated with dominantly inherited non-syndromic hearing loss. The variant, c.34G>T, has been reported in the literature in compound heterozygous state together with other (likely) pathogenic variants in GJB2 in individuals affected with Non-Syndromic Hearing Loss (e.g. Chan_2010, Jiang_2015, Wu_2017 (NO_PMID), Shen_2019, Florentine_2022). In addition, the variant has also been reported in an individual affected with hearing loss who carried a likely pathogenic deletion in GJB6, suggesting that the variant may have contributed to hearing loss by a digenic mechanism in this patient (Raymond_2019). These data indicate that the variant is likely to be associated with disease. Although the variant has been reported in (apparent) heterozygosity in multiple individuals in whom a second mutation was not identified (e.g. Azaiez_2004, Tang_2006, Putcha_2007, Hernandez-Juarez_2014, Jiang_2015, Tayoun_2015, Xiang_2019), however in many of these cases, the GJB2 gene was not completely sequenced, other hearing loss-associated genes were not tested, and/or large rearrangements were not assessed; thus these reports do not provide conclusive evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants at the same amino acid position (G12V/R/D) have been reported in affected individuals (HGMD), and c.35G>T (p.Gly12Val) has been classified as a pathogenic by our laboratory for autosomal recessive non-syndromic hearing loss. The following publications have been ascertained in the context of this evaluation (PMIDs: 15365987, 20154630, 31099403, 25288386, 32090102, 26252218, 17666888, 31163360, 31160754, 26969326, 17041943, 26444186, 31035178, 34515852). 15 other submitters (including an expert panel) have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as pathogenic (n=3) / likely pathogenic (n=11; including the expert panel), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not provided Pathogenic:5
Reported in published literature in the heterozygous state in multiple unrelated individuals with congenital hearing loss (Azaiez et al., 2004; Tang et al., 2006; Hernndez-Jurez et al. 2014); Observed in two heterozygous individuals who reported a family history suggestive of autosomal dominant hearing loss, but no segregation studies were performed for the p.(G12C) variant (Tang et al., 2006; Sloan-Heggen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25262649, 17666888, 25388846, 26969326, 26444186, 15365987, 25288386, 18987669, 26252218, 11912510, 22643125, 22011219, 31163360, 31160754, 30275481, 20154630, 17041943) -
The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with hearing loss. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the GJB2 protein (p.Gly12Cys). This variant is present in population databases (rs104894408, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 20154630, 26969326, 31163360; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44740). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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The c.34G>T p.Gly12Cys variant (rs104894408) is reported in the literature in multiple hearing loss patients (Putcha 2007, Tang 2006, Hernandez-Juarez 2014, Shen 2019). Testing performed at ARUP Laboratories has identified two individuals with hearing loss who carry p.Gly12Cys on the opposite chromosome from a known pathogenic GJB2 variant and a third affected individual homozygous for the p.Gly12Cys variant. In addition, two other variants at this same amino acid (p.Gly12Val, p.Gly12Asp) have been reported in individuals with autosomal recessive nonsyndromic hearing loss and are considered pathogenic (Putcha 2007, Hernandez-Juarez 2014). The glycine at codon 12 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.838). Based on available evidence, the p.Gly12Cys variant is considered to be likely pathogenic. References: Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-2012. Putcha et al. 2007. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet. Med. 9(7):413-26. Tang et al. 2006. 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. 140(22):2401-15. Shen J et al. ClinGen Hearing Loss Working Group. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med. 2019 Nov;21(11):2442-2452. PMID: 31160754. -
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2
GJB2 NM_004004.5 p.Gly12Cys (c.34G>T): This variant has been reported in the literature in at least 6 individuals with hearing loss (Azaiez 2004 PMID: 15365987, Tang 2006 PMID:17041943, Putcha 2007 PMID:17666888, Hernandez-Juarez 2014 PMID:25288386, Raymond 2019 PMID:31163360). On of these patients showed digenic inheritance with a pathogenic deletion of GJB6. However, at least 2 of these individuals did not have an additional disease causing variant identified, and the zygosity of this variant for the other individuals is unclear. This variant is present in 0.3% (129/34098) of Latino alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104894408). This variant is present in ClinVar, with several labs classifying this variant as likely pathogenic or pathogenic (Variation ID: 44740). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic -
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Hearing loss Pathogenic:1
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Nonsyndromic genetic hearing loss Pathogenic:1
The c.34G>T (NM_004004.6) in GJB2 is a missense variant predicted to cause the substitution of glycine by cysteine at amino acid 12 (p.Gly12Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0036 (128/35104 alleles) in the Latino/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss VCEP for autosomal recessive hearing loss variants. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one proband was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID: 15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong). A different pathogenic missense variant (p.Gly12Val) (ClinVar Variation ID 21387) in the same codon of GJB2 has been classified as likely pathogenic and pathogenic for hearing loss by 7 labs who are in concordance that this variant is LP/P (PM5). The computational predictor REVEL gives a score of 0.838, and the nucleotide is heavily conserved in UCSC, which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM3_Very Strong, PM5, PP3, BS1 (ClinGen Hearing Loss VCEP specifications version 2; 10/19/2022) -
Hearing impairment Pathogenic:1
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Mutilating keratoderma Pathogenic:1
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Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
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GJB2-related disorder Pathogenic:1
The GJB2 c.34G>T variant is predicted to result in the amino acid substitution p.Gly12Cys. This variant has been reported in the literature along with a second GJB2 variant in at least three individuals with hearing loss (Chan et al. 2010. PubMed ID: 20154630; Jiang et al. 2015. PubMed ID: 26252218; Supplemental File 2, Florentine et al. 2022. PubMed ID: 34515852) as well as one patient undergoing testing for hearing loss at PreventionGenetics. It has also been reported in the heterozygous state in the absence of a second potentially causative variant in patients with hearing loss, although the completeness of testing the GJB2 gene and upstream regulatory elements as well as other hearing loss related genes in these individuals is unknown (Azaiez et al. 2004. PubMed ID: 15365987; Tang et al. 2006. PubMed ID: 17041943; Putcha et al. 2007. PubMed ID: 17666888). This variant is reported in 0.36% of alleles in individuals of Latino descent in gnomAD, including 1 homozygote. In ClinVar this variant is classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel for autosomal recessive hearing loss, citing internal data from another laboratory in which this variant was observed in the homozygous state or in trans with a second causative variant in five affected individuals (https://www.ncbi.nlm.nih.gov/clinvar/variation/44740/). Another substitution at this amino acid position (p.Gly12Val) has also been reported in individuals with hearing loss (Chan et al. 2010. PubMed ID: 20154630; Rabionet et al. 2000. PubMed ID: 10982180; Figueroa-Ildefonso et al. 2019. PubMed ID: 31370293), and a different substitution (p.Gly12Arg) has been reported in individuals with keratitis-ichthyosis-deafness syndrome (Richard et al. 2002. PubMed ID: 11912510), indicating this position is important for normal protein function. While the clinical significance of this variant is uncertain for autosomal dominant disorders, this variant is interpreted as likely pathogenic for autosomal recessive hearing loss. -
Rare genetic deafness Pathogenic:1
The p.Gly12Cys variant in GJB2 has been previously identified by our laboratory in 7 individuals with hearing loss; one individual was homozygous for the varian t and four individuals had a second pathogenic or likely pathogenic variant in G JB2, supporting an autosomal recessive inheritance pattern. The p.Gly12Cys varia nt has also been reported in the literature in 11 individuals with hearing loss. In 1 individual, a variant affecting the remaining copy of GJB2 was identified; however, in the remaining 10 individuals, a variant affecting the remaining DFN B1 allele was not identified (Tang 2006, Azaiez 2004, Putcha 2007, Mendelsberg-F ishbein 2013, Hernandez-Juarez 2014). Furthermore, this variant has been reporte d in ClinVar and is classified as likely pathogenic by the Hearing Loss Expert P anel (ClinVar Variation ID 44740). This variant was identified in 0.38% (129/340 98) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNPrs104894408). While the frequency data meets the th reshold for likely benign variants when there is no conflicting information, the evidence supporting pathogenicity outweighs the evidence supporting a likely be nign classification. Three other amino acid changes have been reported at this p osition; p.Gly12Arg has been associated with clinical features of an autosomal d ominant form of hearing loss (Keratitis-Ichthyosis-deafness syndrome), and p.Gly 12Val and p.Gly12Asp which have been associated with an autosomal recessive hear ing loss. Glycine (Gly) at position 12 is highly conserved in mammals and evolut ionarily distant species, supporting that a change at this position may not be t olerated. Additional computational prediction tools suggest that the p.Gly12Cys variant may impact the protein. In summary, although additional studies are requ ired to fully establish its clinical significance, this variant meets criteria t o be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/ AMP Criteria applied: PM3_VeryStrong, PM5, PP3. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at