rs28931593

Positions:

chr13-20189358-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.224G>A(p.Arg75Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 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. R75W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

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 18 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

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-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 13-20189358-C-T is Pathogenic according to our data. Variant chr13-20189358-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189358-C-T is described in Lovd as [Pathogenic]. Variant chr13-20189358-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.224G>A	p.Arg75Gln	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.224G>A	p.Arg75Gln	missense_variant	2/2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.224G>A	p.Arg75Gln	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.224G>A	p.Arg75Gln	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2023	Published functional studies demonstrate this variant prevents formation of functional channels (Piazza et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21040787, 20096356, 20815033, 26088551, 20583176, 16059934, 33466560, 23451214, 25393658, 25153233, 29798269, 27316387, 25388846, 24975403, 24945352, 12372058, 29921236, 34599368, 15790391, 33096615, 15996214) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 75 of the GJB2 protein (p.Arg75Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant GJB2-related conditions (PMID: 12372058, 20815033, 24945352, 25153233, 27316387). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17027). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 21040787). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 2005	- -

Palmoplantar keratoderma-deafness syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 30, 2005

- -

Hereditary palmoplantar keratoderma;C5680182:Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 21, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.224G>A, p.Arg75Gln variant is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This variant has been found in 6 families (2 familial cases with dominant hearing loss and palmoplantar keratoderma and 4 families with non-syndromic autosomal dominant hearing loss) and segregated it correctley in all members of the families, meeting PS4_Mod and PP1_Mod (PMID: 12372058, 15790391, 15996214, 16059934,23451214). A previous variant (p.Arg75Trp) has been previously described as causative mutation of syndromic (palmoplantar keratoderma and autosomal dominant hearing loss) and non-syndromic autosomal dominant hearing loss, applying to PM5 rule. Computational evidence predicted the mutation to be damaging to the protein (REVEL= 0.985; PP3). Functional studies in HeLa cells demonstrated that p.Arg75Gln mutant did not present dye transfer (Lucifer Yellow, Neurobiotin and calcein dyes) and showed a dominant effect when it was co-expressed with wtCX26. Besides there was a null electrical coupling (PMID: 15996214, 2104787). In addition to his, it was demonstrated a partial inhibition of neurobiotin when it was co-expressed with wtCX30 applying to PS3_Moderate rule. Therefore, the c.224G>A variant meets criteria to be classified as pathogenic for autosomal dominant non-syndromic hearing loss and syndromic hearing loss (palmoplantar keratoderma and deafness): PM2, PS4_Moderate, PP1_Moderate, PM5, PP3 and PS3_Moderate. -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institut Pasteur du Maroc

Apr 01, 2016

Pathogenic -

Nonsyndromic Deafness

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Sep 04, 2024

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 28, 2013

The Arg75Gln variant in GJB2 has been identified in several individuals with hea ring loss with or without palmoplantar keratoderma, was found to segregate with disease in over 10 affected relatives, and was determined to have occurred de no vo in at least one individual (Uyguner 2002, Feldmann 2005, Posukh 2005, Piazza 2005, Wu 2011). This variant has not been identified in large population studies . In vitro functional studies indicate the Arg75Gln variant may impact protein f unction and acts in a dominant-negative manner (Piazza 2005, Yum 2010, Zhang 201 1). In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;H;H

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.0

D;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.93

MutPred

0.99

Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);

MVP

0.98

MPC

0.30

ClinPred

1.0

GERP RS

5.2

Varity_R

0.98

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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