13-20189581-T-C

Position:

chr13-20189581-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS3_ModeratePM3

This summary comes from the ClinGen Evidence Repository: The c.1A>G (p.Met1Val) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 550716, 2070085, 371781, 551915). The highest population minor allele frequency of the variant is 0.02% (5/30616) in the South Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). Intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID:12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID:26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID:20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID:9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023).intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID:12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID:26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID:20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID:9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA198806/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 start_lost

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 7.86

Variant links:

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]

GJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249172

Hom.:

AF XY:

0.0000593

AC XY:

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	GJB2: PM3:Very Strong, PM2, PVS1:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs111033293, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 9482292, 10218527, 18941476, 20146813). ClinVar contains an entry for this variant (Variation ID: 44729). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GJB2 function (PMID: 12189493). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2022	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that c.1A>G is a null variant (Thonnissen et al., 2002); This variant is associated with the following publications: (PMID: 20146813, 29542069, 9482292, 16950989, 16380907, 20083784, 23695287, 23555729, 16532460, 15488970, 12910486, 10218527, 9710598, 18941476, 29625052, 33504652, 12189493, 18983339) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2021	The GJB2 c.1A>G; p.Met1? variant has been described in the literature in individuals with autosomal recessive hearing loss as compound heterozygote with another GJB2 pathogenic variant or with a GJB6 pathogenic variant (Estivill 1998, Putcha 2007, Snoeckx 2005, Thonnissen 2002). This variant occurs in the initiation codon, the first methionine in the GJB2 protein, and has been shown to not produce a full-length functional protein (Thonnissen 2002). This variant is also reported in ClinVar (Variation ID: 44729). This variant is found in the general population with an overall allele frequency of 0.0036% (10/280566 alleles) in the Genome Aggregation Database. Therefore, this variant is considered pathogenic. References: Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7;351(9100):394-8. 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. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Thönnissen E et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 Aug;111(2):190-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 28, 2024

The c.1A>G (p.Met1Val) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 550716, 2070085, 371781, 551915). The highest population minor allele frequency of the variant is 0.02% (5/30616) in the South Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). Intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). intercellular diffusion of microinjected neurobiotin in coupling-deficient HeLa cells transfected with Connexin 26 cDNAs was analyzed. The transfectant M1V showed reduced neurobiotin transfer compared to wild-type and equivalent to background levels indicating that this variant impacts protein function (PS3_Moderate; PMID: 12189493). This variant has been detected in at least 6 individuals with nonsyndromic hearing loss (4.5 PM3_Very Strong points). Two individuals with nonsyndromic hearing loss were homozygous for the variant (PMID: 26188157, 18941476). One individual with bilateral sensorineural hearing loss was compound heterozygous with a pathogenic variant c.167delT, p.Leu56fs (ClinVar ID: 17010, PMID: 20146813). Another three individuals with nonsyndromic hearing loss were compound heterozygous (one confirmed trans, the other two assumed trans) with the pathogenic c.35delG, p.Gly12fs variant (ClinVar ID: 17004, PMID: 9482292, 10218527, 23555729). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM3_Very Strong, PS3_Moderate (VCEP specifications version 2; 10.24.2023). -

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

Feb 14, 2022

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2016

The c.1A>G in GJB2 has been reported in at least 8 individuals with nonsyndromic hearing loss and segregated with disease in 1 family member (Estivill 1998, Tho nnissen 2002, Snoeckx 2005, Gardner 2006, Bajaj 2008). Many of these individuals were either homozygous or compound heterozygous. In addition, this variant has now been identified by our laboratory in 4 individuals with hearing loss who wer e also compound heterozygous for another pathogenic variant affecting the other copy of GJB2. This variant has been identified in 2/66508 European chromosomes i n the heterozygous state by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs111033293). It alters the start codon, and is there fore predicted to disrupt translation. An in vitro functional study provides som e evidence that that this variant might result in complete absence of protein (T honnissen 2002). In summary, this variant meets our criteria to be classified as pathogenic in an autosomal recessive manner. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D

PROVEAN

Uncertain

-3.7

D;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.020

D;D;.

Polyphen

0.97

D;D;D

Vest4

0.94

MVP

0.98

ClinPred

0.80

GERP RS

5.1

Varity_R

0.93

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over