13-20189473-C-T

Position:

• chr13-20189473-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3 PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 gene is 7.9% for East Asian genomes in gnomAD.This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). 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 BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID:31160754). This study also reported the variant in 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID:31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID:31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID:27308859). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID:26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID:27623246). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172210/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0040 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (83 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:49 U:1 B:1 O:1
• Conservation: PhyloP100: 6.10

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.109G>A	p.Val37Ile	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.109G>A	p.Val37Ile	missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.109G>A	p.Val37Ile	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.109G>A	p.Val37Ile	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152178 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0705

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00772 AC: 1936 AN: 250766 Hom.: 90 AF XY: 0.00681 AC XY: 924 AN XY: 135584

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00806

Gnomad EAS exome AF: 0.0827

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00237 AC: 3462 AN: 1461390 Hom.: 83 Cov.: 33 AF XY: 0.00222 AC XY: 1616 AN XY: 726914

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00774

Gnomad4 EAS exome AF: 0.0415

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.000858

Gnomad4 OTH exome AF: 0.00679

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152296 Hom.: 18 Cov.: 33 AF XY: 0.00435 AC XY: 324 AN XY: 74470

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0707

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00366 Hom.: 20

Bravo AF: 0.00451

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00658 AC: 799

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:49 Uncertain:1 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:21 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_004004.5(GJB2):c.109G>A(V37I) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with slowly progressive bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 12121355, 16840571, 16300957, 17935238, 10633133 and 15479191. Classification of NM_004004.5(GJB2):c.109G>A(V37I) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 04, 2022	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 23, 2015	This patient is a carrier of a heterozygous pathogenic variant in the GJB2 gene associated with autosomal recessive deafness 1A. The GJB2 variant (c.109G>A; p.V37I) identified in this patient is a missense variant reported to be a common pathogenic variant in individuals with Asian ancestry and is associated with mild to moderate, sometimes progressive hearing impairment in individuals with various ages. (Gallant et al. 2013, PMID: 23873582; Huculak et al. 2006, PMID: 17036313; Bruzzone et al. 2003, PMID: 12505163; Li et al. 2012, PMID: 22574200) -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31160754, PM3_M). It was co-segregated with Deafness, autosomal recessive 1A in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 16300957, 27308859, 26088551, 12505163, 31160754, 27623246) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 31160754, PS4_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 12505163, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.656, 3CNET: 0.929, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000179256,VCV000449490, PMID:15365987,17666888, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 10, 2023	ACMG classification criteria: PS4 strong, PM3 moderated, PP1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 11, 2020	This GJB2 variant has been vetted by the ClinGen Hearing Loss Expert Panel and is predicted to be associated with autosomal recessive sensorineural hearing loss that is typically mild to moderate and bilateral. GJB2 c.109G>A (rs72474224) reaches polymorphic frequency (>1%) within the East Asian subpopulation in a large population dataset6 (gnomAD: 1665/19952 alleles; 8.3%, 96 homozygotes), however, it was found to be significantly overrepresented in hearing loss patients compared to population controls. This variant was found to segregate with hearing loss in a large number of families. Functional studies suggest that GJB2 c.109G>A impacts connexin 26 function, however, this has not been confimed to reflect the biologic process in human cochlea. We consider this variant to be pathogenic. -
Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 01, 2024	This sequence change is predicted to replace valine with isoleucine at codon 371 of the GJB2 protein, p.(Val37Ile). The valine residue is highly conserved (100 vertebrates, Multiz alignments), and located in the connexin domain. There is a small physicochemical difference between valine and isoleucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 4.5% (2,013/44,852 alleles, 90 homozygotes) in the East Asian population, which is higher than expected for a recessive disease. The prevalence of the variant in individuals with nonsyndromic deafness is significantly increased compared with the prevalence in controls (PMID: 31160754). The variant has been identified as compound heterozygous with a second pathogenic allele in more than a hundred individuals and homozygous in more than a hundred individuals, typically manifesting with mild to moderate hearing loss (PMID: 31160754). The variant segregates in at least 21 affected siblings over multiple families (PMID: 31160754). Additionally, in vitro functional studies of the variant demonstrate impaired function (PMID: 12505163, 16300957, 26088551). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.656). Based on the classification scheme RMH ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC, with reduced penetrance. Following criteria are met: PP1_Strong, PM3_VeryStrong, PS3_Supporting, PP3, BS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GJB2 c.109G>A (p.Val37Ile) missense variant is widely reported in the literature. The variant was first identified in a compound heterozygous state with a second variant in a single individual with hearing loss (Abe et al. 2000). Pollak et al. (2007) found the variant was significantly overrepresented in individuals with hearing loss as compared to controls (5.2% compared to 0.43%) and suggested that this variant might cause a late onset, mild form of hearing loss with reduced penetrance when found in combination with other variants in the GJB2 gene. In an evaluation of over 1000 newborns, Wu et al. (2011) identified several homozygotes and compound heterozygotes for the p.Val37Ile variant, with both normal hearing and varying degrees of hearing loss. Expression studies have demonstrated that the p.Val37Ile variant results in a complete loss of homotypic gap junction channel activity (Snoeckx et al. 2005). The p.Val37Ile variant is reported at a frequency of 0.08586 in the Kinh in Ho Chi Minh City, Vietnam, population of the 1000 Genomes Project. This frequency is high but may be consistent with the prevalence of mild hearing loss in the population. Based on the collective evidence, the p.Val37Ile variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss, though is associated with a mild phenotype and reduced penetrance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2018	Variant summary: GJB2 c.109G>A (p.Val37Ile) results in a conservative amino acid change located in the Connexin, N-terminal of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0074 in 280234 control chromosomes in the gnomAD database, including 91 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.0074 vs 0.025), allowing no conclusion about variant significance. This variant was first listed as a polymorphism by Kelley_1998 due to finding of one heterozygote of this variant in 96 control persons. However, all following studies on genotype-phenotype in patients and gene function suggest that this variant is pathogenic. In hearing loss patients with this variant, clinical severity ranges from mild to moderate. In a Chinese study (Chai_2015), the variant was strongly associated with both mild-to-moderate (p=2.01011) and severe-to-profound (p=0.001) HI, but was estimated to have a rather low penetrance (17%). Huang_2015 showed that among the 3,864 Chinese patients, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). Homozygotes of this variant or compound heterozygotes of this variant and a pathogenic variant in GJB2 were reported in patients with hearing loss in populations other than East Asian (Robionet_2000, Wilcox_2000, Snoeckx_2005). In vitro junctional conductance and biochemical permeability study on mutant Cx26 V37I showed the function of Cx26 V37I was significantly decreased (Bruzzone_2003 and Kim_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight of these have reported a classification as pathogenic (n=7) or likely pathogenic (n =1). This is consistent with the results of the "Clingen hearing loss variant curation expert panel" that has settled upon a classification for this variant as "Pathogenic" based on compelling statistical and supporting functional evidence (personal correspondence, manuscript in preparation at this time of classification) . Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.109G>A;p.(Val37Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 17023: PMID: 31160754; 23637863; 29926981) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26088551, 12505163, 16300957; 26088551; 31562289) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Connexin) - PM1. The p.(Val37Ile) was detected in trans with a pathogenic variant (PMID: 31160754; 26088551; 24654934; 23637863; 29926981) - PM3_very strong Pathogenic missense variant in this residue have been reported (Clinvar ID: 179256; 449490) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 31160754; 26088551; 23637863) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Uncertain significance, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Oct 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 29, 2017	A homozygous missense variant was identified, NM_004004.5(GJB2):c.109G>A in exon 2 of the GJB2 gene.This substitution is predicted to create a minor amino acid change from valine to a isoleucine at position 37, NP_003995.2(GJB2):p.(Val37Ile). The valine at this position has very high conservation (100 vertebrates, UCSC).In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster) and it is not situated in a specific functional domain. This variant is present in the gnomAD population database at a frequency of 0.7% (2011 in 276450, 91 homozygotes) with an increased frequency in East Asian populations at 8.2% (1546 in 18868, 88 homozygotes). It is a variant with variable penetrance and has been reported in patients with mild to moderate hearing loss, sometimes progressive (Huang, Y. et al. (2015), Chai, Y.et al. (2014), Shen, N. et al. (2017), ClinVar). Based on current information, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.109G>A in Exon 2 of the GJB2 gene that results in the amino acid substitution p.Val37Ile was identified. The observed variant has a minor allele frequency of 0.00772/0.00624% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 17023]. The variant has previously been reported for deafness by Shen, Jun, et al., 2019. Experimental studies have shown that this missense change disrupts the formation of homotypic junctional channels in vitro by Chen, Ying, et al., 2016. For these reasons this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 25, 2024	Criteria applied: PS3_MOD,PM3_VSTR,PM5_STRPP1_VSTR,PP3 -

not provided Pathogenic:13

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Case control studies suggest this variant is associated with hearing loss; homozygous and compound heterozygous genotypes are statistically enriched in individuals with autosomal recessive nonsyndromic hearing loss compared to the general population (PMID: 31160754); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (PMID: 31160754, 26582918); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16380907, 15070423, 15479191, 22975760, 22995991, 12792423, 10830906, 19586875, 30473554, 17036313, 25087612, 30609409, 34416374, 30311386, 34943631, 23638949, 24645897, 9529365, 25262649, 17935238, 23873582, 24654934, 12505163, 22613756, 24158611, 22106692, 24212883, 16300957, 19707039, 24945352, 22574200, 23637863, 26088551, 16840571, 17041943, 10633133, 12121355, 22567861, 27623246, 27792752, 19043807, 26885124, 26061099, 27153395, 26896187, 27308839, 26104599, 25388846, 28012523, 28901477, 28786104, 26990548, 26119842, 16952406, 29921236, 29287868, 28489599, 30094485, 30693673, 31195736, 31370293, 30733538, 31180159, 30344259, 30146550, 31914302, 31541171, 31827275, 31980526, 32386258, 30896630, 33724713, 32645618, 30872718, 34062854, 33597575, 33638616, 30828346, 34426522, 34192699, 33096615, 32067424, 33095980, 31078570, 35861108, 37248651, 36190904, 34515852, 37838930, 35853923, 37070846, 35939872, 36597107, 36515421, 34519870, 38069086, 35734583, 36453950, 35982127, 36048236, 37271870, 38254107, 35816303, 35314707, 34403091, 35478332, 36147510, 35611242, 34599368, 35016843, 35114279, 34032567, 31160754, 27535533, 26582918) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	GJB2: PM3:Very Strong, PP1:Strong, PM2, PM5, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ile). This variant is present in population databases (rs72474224, gnomAD 8%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in the literature in a large meta-analysis involving several thousand cases and controls (PMID: 28489599). This variant has been reported frequently in individuals affected with mild to moderate deafness particularly among populations in eastern Asia (PMID: 23637863, 26885124, 26061099, 17036313, 16952406, 21488715). It has been shown to segregate with autosomal recessive deafness in families (PMID: 28489599, 24945352, 26088551). Although this variant is more common in the population than expected for a pathogenic variant, the penetrance of this variant is estimated to be less than 20% of other disease-causing variants in GJB2 (PMID: 17935238, 24654934). ClinVar contains an entry for this variant (Variation ID: 17023). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change disrupts the formation of homotypic junctional channels in vitro (PMID: 12505163). Furthermore in vivo knock-in and knock-out mouse models recapitulate the deafness phenotype observed in humans (PMID: 27623246). In summary, this variant is reported to cause sensorineural deafness. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the GJB2 gene, it has been classified as Pathogenic (low penetrance). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 26, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2023	This variant is one of the most common variants associated with nonsyndromic hearing loss and is reported to have reduced penetrance in some families (PMID: 31160754, 30311386, 28489599). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been reported in individuals with autosomal recessive nonsyndromic hearing loss and deafness. Heterozygous individuals with hearing loss have also been reported. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experimental studies demonstrate that this variant impairs homotypic junctional channel formation (PMID: 12505163, 16300957). -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	The GJB2 c.109G>A; p.Val37Ile variant (rs72474224) is reported in the literature in multiple individuals affected with hearing loss (Baux 2017, Kecskemeti 2018, Posukh 2019, Putcha 2007, Zhou 2019). However, homozygosity for p.Val37Ile has been associated with normal hearing (Tang 2006) as well as with slight, mild or moderate hearing loss, primarily in individuals of Asian background (Bason 2002, Dahl 2006, Kim 2015, Kim 2013, Pollak 2007, Rabionet 2000). The p.Val37Ile variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 17023) and has been shown to disrupt protein function using a Xenopus oocyte-based gap junction formation assay (Bruzzone 2003) and a gap junction permeability assay in HEK293 cells (Kim 2015). This variant is found predominantly in the East Asian population with an allele frequency of 8.3% (1665/19952 alleles, including 96 homozygotes) in the Genome Aggregation Database. Additionally, other variants at this codon (c.110T>C; p.Val37Ala and c.109G>C; p.Val37Leu) have been reported in individuals with sensorineural hearing loss (Azaiez 2004, Putcha 2007). Based on available information, this variant is considered to be mildly pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 24:305-311. Bason L et al. Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss. Clin Genet. 2002 61:459-464. Baux D et al. Combined genetic approaches yield a 48% diagnostic rate in a large cohort of French hearing-impaired patients. Sci Rep. 2017 7:16783. Bruzzone R et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533:79-88. Dahl HH et al. The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet. 2006 43:850-855. Kecskemeti N et al. Analysis of GJB2 mutations and the clinical manifestation in a large Hungarian cohort. Eur Arch Otorhinolaryngol. 2018 275:2441-2448. Kim J et al. Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene. Exp Mol Med. 2015 47:e169. Kim SY et al. Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. PLoS One. 2013 8:e61592. Pollak A et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007 143A:2534-2543. Posukh OL et al. Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes (Basel). 2019 10. 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 9:413-426. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 106:40-44. Tang HY 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 140:2401-2415. Zhou Y et al. Mutation analysis of common deafness genes among 1,201 patients with non-syndromic hearing loss in Shanxi Province. Mol Genet Genomic Med. 2019 7:e537. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	PP1_strong, PM3, PS4 -

Nonsyndromic genetic hearing loss Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	INGEBI, INGEBI / CONICET	Aug 31, 2020	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 03, 2024	The p.Val37Ile variant in GJB2 is a well established allele that is known to be pathogenic in the homozygous state or in the compound heterozygous state with another pathogenic GJB2 variant and typically results in a mild to moderate hearing loss (Snoeckx 2005 PMID: 16380907, Huculak 2006 PMID: 17036313, Pollak 2007 PMID: 17935238). In rare cases, it may even be associated with normal hearing. Additionally, it has been reported as pathogenic in ClinVar by the ClinGen Hearing Loss Expert panel (Variation ID 17023; Shen 2019 PMID: 31160754). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss. ACMG/AMP Criteria applied: PP1_Strong, PM3_VeryStrong. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jun 24, 2019	The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 gene is 7.9% for East Asian genomes in gnomAD.This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). 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 BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID: 31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID: 31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID: 27308859). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID: 26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID: 27623246). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3. -

Hearing impairment Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PS1_Very strong, PM3_Supporting, PM5_Moderate, PP3_Supporting -

GJB2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as homozygous and compound heterozygous change in patients with deafness (PMID: 31160754, 9529365, 10982180, 12121355, 16380907, 16840571, 17036313, 17041943, 17935238). Functional studies have shown a damaging effect of the variant on intercellular biochemical permeability and conductance (PMID: 12505163). This variant has been classified as Pathogenic by ClinGen Expert Panel (PMID: 31160754; ClinVar). The c.109G>A (p.Val37Ile) variant is present in the heterozygous state in the gnomAD population database in 2132/282164 individuals and homozygous state in 99 individuals, with a total allele frequency of 0.7%. Based on the available evidence, the c.109G>A (p.Val37Ile) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 25, 2024	The GJB2 c.109G>A variant is predicted to result in the amino acid substitution p.Val37Ile. This variant in the homozygous state has been reported to be strongly associated with both mild-to-moderate (P=2.0×10-11) and severe-to-profound (P=0.001) hearing impairment, but was estimated to have a low penetrance (17%). Onset of hearing loss was 65% congenital and 35% delayed in individuals that were homozygous for c.109G>A (Chai et al. 2015. PubMed ID: 24654934). This variant has also been reported to cause nonsyndromic hearing loss in the compound heterozygous state with a second disease causing GJB2 variant (Abe et al. 2000. PubMed ID: 10633133). The c.109G>A variant has been reported at a subpopulation frequency of up to 8.2% in a database of individuals with unknown phenotype, which is unusually high for a pathogenic variant. However, a ClinGen Hearing Loss expert panel has classified this variant as pathogenic for autosomal recessive nonsyndromic hearing loss, noting hearing loss is typically mild with incomplete and possibly age-related penetrance (https://www.ncbi.nlm.nih.gov/clinvar/variation/17023/; Shen et al. 2019. PubMed ID: 31160754). This variant is interpreted as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2021	- -
Likely benign, flagged submission	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2020

The c.109G>A (p.V37I) alteration is located in coding exon 1 of the GJB2 gene. This alteration results from a G to A substitution at nucleotide position 109, causing the valine (V) at amino acid position 37 to be replaced by an isoleucine (I)._x000D_ _x000D_ update for allelic disease - AD is too common Based on data from gnomAD, the A allele has an overall frequency of 0.756% (2132/282164) total alleles studied. The highest observed frequency was 8.345% (1665/19952) of East Asian alleles. This alteration has been more commonly reported in individuals of Asian ancestry (both affected and controls) (Huculak, 2006; Tang, 2006; Li, 2012). Although rare, homozygous and compound heterozygous observations have been identified in individuals with normal hearing; however presentation is typically associated with childhood onset bilateral sensorineural hearing loss (Shen, 2019; Tang, 2006). A more recent study has reported the p.V37I variant as pathogenic with variable expressivity and incomplete penetrance with progressive hearing loss over time when detected in homozygous or compound heterozygous forms (Chen, 2020). This variant has been detected as a homozygous finding in multiple families with sensorineural hearing loss (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate an inability to induce formation of homotypic gap-junction channels, leading to a complete loss of channel activity (Bruzzone, 2003). However, large cohort studies have reported that hearing loss is typically in the mild to moderate range suggesting that the phenotypic presentation may not reflect the functional data (Snoeckx, 2005; Huculak, 2006). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

Nonsyndromic Deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Aug 05, 2016

- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Human Genetics, Universidade de São Paulo

-

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Uncertain	0.67	D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;.;D
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.82	N;N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.72	T;T;.
Sift4G	Benign	0.51	T;T;.
Polyphen		1.0	D;D;D
Vest4		0.26
MVP		0.67
MPC		0.043
ClinPred		0.049	T
GERP RS		5.2
Varity_R		0.42
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs72474224; hg19: chr13-20763612;