rs104894409

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM5PP3_StrongPP5_Very_Strong

The ENST00000382848.5(GJB2):c.250G>T(p.Val84Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,806 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

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

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 24 ACMG points.

PS1

Transcript ENST00000382848.5 (GJB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 17032

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in ENST00000382848.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189332-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 13-20189332-C-A is Pathogenic according to our data. Variant chr13-20189332-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 167134.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.250G>T	p.Val84Leu	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.250G>T	p.Val84Leu	missense_variant	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.250G>T	p.Val84Leu	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.250G>T	p.Val84Leu	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251338

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS1+PM3_Strong+PS3_Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 03, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 03, 2020	Variant summary: GJB2 c.250G>T (p.Val84Leu) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251338 control chromosomes (gnomAD). c.250G>T has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Kenna_2001, Wu_2002, Snoeckx_2005, Putcha_2007, Minami_2013, Carranza_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant retains electrophysiological properties but affects the intercellular exchange of large molecules (such as IP3 transfer) (e.g. Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	Published functional studies demonstrate the variant interferes with the metabolic coupling function of the GJB2 protein (Beltramello et al., 2005); This variant is associated with the following publications: (PMID: 12189487, 14985372, 20441744, 12505163, 12562518, 11556849, 9529365, 15592461, 26346709, 16380907, 17426645, 17666888, 31160754) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 11556849, 12172394, 16380907, 19235794, 24013081, 26346709). ClinVar contains an entry for this variant (Variation ID: 167134). 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: 12505163, 12562518, 15592461, 16217030, 20441744). For these reasons, this variant has been classified as Pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 30, 2019

The GJB2 c.250G>T; p.Val84Leu variant (rs104894409), as well as another variant generating the same amino acid substitution (c.250G>C; p.Val84Leu), are reported in the literature in multiple individuals affected with nonsyndromic hearing loss (NSHL) (Cryns 2004, Snoeckx 2005), including individuals also carrying the pathogenic c.35delG variant (Putcha 2007). The c.250G>T; p.Val84Leu variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 167134), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 84 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional tests indicate that, while the variant protein can form functional channels capable of electrical coupling (Ambrosi 2010, Bruzzone 2003), the p.Val84Leu substitution results in reduced permeability to inositol 1,4,5-trisphosphate (Beltramello 2005). Based on available information, this variant is considered to be pathogenic. References: Ambrosi et al. Analysis of four connexin26 mutant gap junctions and hemichannels reveals variations in hexamer stability. Biophys J. 2010 98(9): 1809-1819. Beltramello et al. Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol. 2005 7(1):63-69. Bruzzone et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533(1-3): 79-88. Cryns et al. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004 41(3): 147-154. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 9(7): 413-426. Snoeckx et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 77(6): 945-957. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.96

MutPred

0.98

Loss of glycosylation at S85 (P = 0.0994);Loss of glycosylation at S85 (P = 0.0994);Loss of glycosylation at S85 (P = 0.0994);

MVP

0.98

MPC

0.28

ClinPred

0.97

GERP RS

5.3

Varity_R

0.90

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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