rs104894402

Variant names:

• chr13-20189359-G-A
• rs104894402
• NM_004004.6:c.223C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-20189359-G-A
• chr13-20189359-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004004.6(GJB2):​c.223C>T​(p.Arg75Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R75G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.75
• Publications: 104 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 19 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189359-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 560666.Status of the report is no_assertion_criteria_provided, 0 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, 0.993
• PP5: Variant 13-20189359-G-A is Pathogenic according to our data. Variant chr13-20189359-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17011.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.223C>T	p.Arg75Trp	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.223C>T	p.Arg75Trp	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.223C>T	p.Arg75Trp	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.223C>T	p.Arg75Trp	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3779C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB2 c.223C>T; p.Arg75Trp variant (rs104894402) is reported in the literature in multiple individuals and families affected with either syndromic or nonsyndromic autosomal dominant hearing loss (ADHL), including some individuals with palmoplantar keratoderma (Lee 2010, Pang 2014, Richard 1998, Weegerink 2011, Yuan 2009). This variant is reported in ClinVar (Variation ID: 17011), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.224G>A; p.Arg75Gln) has been reported in individuals with ADHL and is considered pathogenic (Pang 2014). The arginine at codon 75 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show that arginine 75 is critical to the formation of gap junctions, and variants at this codon have dominant negative effects (Deng 2006, Marziano 2003, Richard 1998, Zhang 2011). Based on available information, the p.Arg75Trp variant is considered to be pathogenic. References: Deng Y et al. Mutations of connexin 26 at position 75 and dominant deafness: essential role of arginine for the generation of functional gap-junctional channels. Hear Res. 2006 Oct;220(1-2):87-94. Lee JY et al. Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of Connexin 26. J Korean Med Sci. 2010 Oct;25(10):1539-42. Marziano NK et al. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet. 2003 Apr 15;12(8):805-12. Pang X et al. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans. PLoS One. 2014 Jun 19;9(6):e100483. Richard G et al. Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet. 1998 Oct;103(4):393-9. Weegerink NJ Phenotypes of two Dutch DFNA3 families with mutations in GJB2. Ann Otol Rhinol Laryngol. 2011 Mar;120(3):191-7. Yuan Y et al. A de novo GJB2 (connexin 26) mutation, R75W, in a Chinese pedigree with hearing loss and palmoplantar keratoderma. Am J Med Genet A. 2009 Feb 15;149A(4):689-92. Zhang J et al. Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26. Mol Cell Neurosci. 2011 Jun;47(2):71-8. -

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 75 of the GJB2 protein (p.Arg75Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant GJB2-related conditions (PMID: 9856479, 24945352). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17011). 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: 9856479). This variant disrupts the p.Arg75 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12372058, 21040787, 24945352). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jul 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (exerts a dominant negative effect on co-expressed wildtype protein, alters Cx26 channel activity, and delays apoptosis) (Rouan et al., 2001; Zhang et al., 2011; Inoshita et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20890442, 17462767, 9856479, 12384501, 25388846, 12668604, 12064628, 18924167, 14681039, 18941476, 16009703, 11493646, 21040787, 20096356, 26763877, 21510145, 18793701, 17666888, 16945493, 12700168, 20301708, 34440452, 30168495, 33096615, 20583176, 24945352, 11354642, 24387126) -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Palmoplantar keratoderma-deafness syndrome Pathogenic:1

Apr 22, 2020

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary palmoplantar keratoderma;C5680182:Nonsyndromic genetic hearing loss Pathogenic:1

Aug 21, 2020

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.223C>T, p.Arg75Trp is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. It was found in 1/154 Egyptian controls who did not show skin disease but they had not been tested for hearing loss (PMID: 9856479) so that this evidence was not counted. The novo confirmed occurrences have been detected in two sporadic non-syndromic hearing loss cases (PMID: 11354642, 2151045) and three syndromic cases (hearing loss and palmoplantar keratoderma; PMID: 18924167, 24945352), meeting PS2_VeryStrong criteria. The p.Arg75Trp change has segregated in three different families with palmoplantar keratoderma and hearing impairment (PMID: 9856479, 20890442, 24945352) applying to PP1_Supporting rule. Besides, this variant was detected in heterozygous state in several sporadic non-syndromic hearing loss patients (PMID: 10980526, 17666888, 18941476) meeting PS4_Moderate criteria. Computational evidence predicted that the mutation has a damaging impact to the protein (REVEL=0.97; PP3). Functional studies in HeLa cells (dye transfer assays) demonstrated a dominant effect of p.Arg75Trp mutant when it was co-injected with CX26WT and CX30WT (completely inhibition of dye transfer); PMID: 12668604, 18941476. In addition to this, functional studies also showed that p.Arg75Trp mutant was incapable of inducing electrical conductance between adjacent cells and it almost completely suppressed the activity of co-expressed WT protein in Xenopus laevis oocytes (PMID: 9856479). Furthermore, transgenic mice expressing R75WCX26 mutant showed severe-profound hearing loss, deformity of supporting cells failure in the formation of the tunnel of Corti and degeneration of sensory hair cells (PMID:12700168) and it was demonstrated its importance for the postnatal development of the organ of Corti and normal hearing (PMID:18793701). Therefore, the c.223C>T variant meets criteria to be classified as pathogenic for autosomal dominant non-syndromic hearing loss and syndromic hearing loss (palmoplantar keratoderma and deafness) (PM2, PS2_VeryStrong, PS4_Moderate, PP1_Supporting, PP3 and PS3_Strong). -

Hearing loss, autosomal recessive Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Rare genetic deafness Pathogenic:1

Sep 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg75Trp variant in GJB2 has been identified as the only GJB2 variant in a t least 11 individuals with hearing loss and was not identified in 120 Indian co ntrol chromosomes and 802 Chinese control chromosomes (Richard 1998, Putcha 2007 , Mani 2009, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014 and LMM unpublished data). Most reported individuals had severe to profound hearing loss that was ei ther congenital or progressive in infancy and some individuals also had palmopla ntar keratoderma. This variant occurred de novo in 3 individuals and was identif ied in three affected parents, which supports that this variant is inherited in a dominant manner (Richard 1998, Yuan 2009, Lee 2010, Weegerink 2011, Pang 2014) . This variant has not been identified in large population studies. Furthermore, Arginine at position 75 is highly conserved across species and other analogous connexin proteins (Deng, 2006). The functional assay demonstrated that the chan ge to a Tryptophan (Trp) at position 75 has a dominant negative affect on the pr otein and disrupts the function of the gap junction (Richard 1998, Maziano 2003, Deng 2006, Zhang 2011) and is important for the postnatal development of the or gan of Corti and normal hearing (Inoshita 2008, Inoshita 2014). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner s.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;H
PhyloP100		3.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-8.0	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.96
MutPred		0.98		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.98
MPC		0.29
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.11	Neutral
Varity_R		0.98
gMVP		0.98
Mutation Taster		=4/96	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: rs104894402; hg19: chr13-20763498;