rs143343083

Positions:

chr13-20189284-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_004004.6(GJB2):c.298C>T(p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H100P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 8.06

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 14 ACMG points.

PM1

In a helix (size 29) in uniprot entity CXB2_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_004004.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189283-T-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

PP5

Variant 13-20189284-G-A is Pathogenic according to our data. Variant chr13-20189284-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.298C>T	p.His100Tyr	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 linkuse as main transcript	c.298C>T	p.His100Tyr	missense_variant	2/2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.298C>T	p.His100Tyr	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 linkuse as main transcript	c.298C>T	p.His100Tyr	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250900

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461580

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GJB2: PM3:Very Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2021	Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); Different missense changes at this residue (p.(H100L), p.(H100P), p.(H100Q)) have been reported as pathogenic in the published literature in association with autosomal recessive nonsyndromic hearing loss (Snoeckx et al., 2005; Bartsch et al., 2010; Kim 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: 25087612, 10376574, 31160754, 25388846, 20553101, 14694360, 17935238, 21287563, 12865758, 11102979, 17666888, 16950989, 17041943, 16380907, 21465647, 31980526, 16931589, 26778469, 16467727, 26749107, 20234132) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 100 of the GJB2 protein (p.His100Tyr). This variant is present in population databases (rs143343083, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11102979, 16222667, 16467727, 17041943, 20553101, 21094084, 21287563, 21465647). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 158607). 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) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2020	The GJB2 c.298C>T; p.His100Tyr variant (rs143343083) has been reported multiple times in the literature in individuals with hearing loss who were compound heterozygous with another pathogenic GJB2 variant (Dodson 2011, Green 1999, Putcha 2007, Siemering 2006, Snoeckx 2005). Additionally, functional studies suggest the variant protein is unable to function properly as a homotypic gap junction (Kim 2016). This variant has also been reported to the ClinVar database (Variation ID: 158607). It is found in the general population with an overall allele frequency of 0.001% (3/250900 alleles) in the Genome Aggregation Database. The histidine at codon 100 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Kim HR et al. The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. Hum Genet. 2016 Mar;135(3):287-98. 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. Siemering K et al. Detection of mutations in genes associated with hearing loss using a microarray-based approach. J Mol Diagn. 2006 Sep;8(4):483-9. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	Variant summary: The GJB2 c.298C>T (p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016). The variant was found in the control population dataset of ExAC in 5/121260 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in multiple patients with NSHL (Putcha_2007, Feldmann_2004, Lipan_2011, Burke_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -

nonsyndromic sensorineural hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Aug 15, 2020

- -

Hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Feb 14, 2003

- -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

GJB2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The GJB2 c.298C>T variant is predicted to result in the amino acid substitution p.His100Tyr. This variant has been reported as causative for autosomal recessive nonsyndromic hearing loss (Green et al. 1999. PubMed ID: 10376574; Dodson et al. 2011. PubMed ID: 21465647; Pollak et al. 2007. PubMed ID: 17935238; Pandya et al. 2003. PubMed ID: 12865758; Cheng et al. 2005. PubMed ID: 16222667; Snoeckx et al 2005. PubMed ID: 16380907; Lipan et al. 2011. PubMed ID: 21287563; Prasad et al. 2000. PubMed ID: 11102979). In vitro studies found this variant is nonfunctional as a homotypic gap junction (Kim et al. 2016. PubMed ID: 26749107). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2016

The p.His100Tyr variant in GJB2 has been reported in >15 individuals with hearin g loss including >10 in the compound heterozygous state (Green 1999, Prasad 2000 , Pandya 2003, Feldmann 2004, Snoeckx 2005, Propst 2006, Tang 2006, Pollack 2007 , Putcha 2007, Siem 2010, Gordon 2011, Schimmenti 2011, Lipan 2011, Schimmenti 2 011). It has been identified in 3/66672 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143343083). Addi tional amino acid changes at this location (p.His100Pro, p.His100Leu, and p.His1 00Gln) have been reported in individuals with hearing loss, suggesting that a ch ange at this location may not be tolerated (Gardner 2006, Snoeckx 2005, Bartsch 2010). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.75

.;.;T

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Pathogenic

0.80

Sift

Benign

0.053

T;T;.

Sift4G

Uncertain

0.050

T;T;.

Polyphen

0.99

D;D;D

Vest4

0.78

MVP

0.97

MPC

0.16

ClinPred

0.94

GERP RS

5.3

Varity_R

0.77

gMVP

0.89

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

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