rs143343083

Variant names:

• chr13-20189284-G-A
• rs143343083
• NM_004004.6:c.298C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H100L) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 8.06
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189283-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 633242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 1A, ichthyosis, hystrix-like, with hearing loss, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, Bart-Pumphrey syndrome, palmoplantar keratoderma-deafness syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss, KID syndrome.
• 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 Pathogenic. ClinVar VariationId is 158607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.298C>T	p.His100Tyr	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.298C>T	p.His100Tyr	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.298C>T	p.His100Tyr	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.298C>T	p.His100Tyr	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3704C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250900 AF XY: 0.00

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 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.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727088

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74286

African (AFR) AF: 0.0000483 AC: 2 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000525 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Dec 14, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB2: PM3:Very Strong, PM2 -

Feb 27, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4

Jul 07, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 11, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 02, 2023

Integrating Genomics into Medicine, Frazer Institute, University Of Queensland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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. -

nonsyndromic sensorineural hearing loss Pathogenic:1

Aug 15, 2020

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hearing loss Pathogenic:1

Feb 14, 2003

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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:1

Feb 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing impairment Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GJB2-related disorder Pathogenic:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
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	D
LIST_S2	Benign	0.75	.;.;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
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	D
GERP RS		5.3
PromoterAI		0.037	Neutral
Varity_R		0.77
gMVP		0.89
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs143343083; hg19: chr13-20763423;