chr13-20189547-C-A

Position:

chr13-20189547-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The ENST00000382848.5(GJB2):c.35G>T(p.Gly12Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,591,136 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. G12C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GJB2
ENST00000382848.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 7.85

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 16 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000382848.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20189548-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44740.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 13-20189547-C-A is Pathogenic according to our data. Variant chr13-20189547-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189547-C-A is described in Lovd as [Pathogenic]. Variant chr13-20189547-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.35G>T	p.Gly12Val	missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3 linkuse as main transcript	c.35G>T	p.Gly12Val	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.35G>T	p.Gly12Val	missense_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.35G>T	p.Gly12Val	missense_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

150236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000922

AC:

AN:

249434

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000312

AC:

AN:

1440900

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

717000

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000700

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000101

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000266

AC:

AN:

150236

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000265

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ExAC

AF:

0.0000500

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 26, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 09, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.35G>T;p.(Gly12Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 21387; PMID: 20301449; 24158611; 19371219; 10982180; 25288386; 17666888) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12176036, 11032405, 25625422) - PS3. The variant is present at low allele frequencies population databases (rs1801002– gnomAD 0.0002662%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 1A, AR, DD (MIM#220290). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 23 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 127 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is intramembrane (Uniprot), located in the N-terminal region of the annotated connexin domain (DECIPHER, NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been classified multiple times as likely pathogenic and pathogenic for biallelic non-syndromic hearing loss and has been shown to have a loss of function effect (ClinVar, GeneReviews, PMID: 29311818). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2016	Variant summary: The GJB2 c.35G>T (p.Gly12Val) variant involves the alteration of a conserved nucleotide. Gly12 lies in an intracellular domain 1 (IC1) and is a known hot spot codon for recurrent disease-causing mutations. Multiple disease-causing variants are found on this codon: c.35delG (the most common DV), c.35dupG, G12R, G12D, and G12C. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/119884 control chromosomes at a frequency of 0.00005, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in several nonsyndromic hearing loss patients in the literature in either homozygous or compound homozygous state with other pathogenic variants which is consistent with pathogenic role in recessive module. In addition, according to an in vitro study (DAndrea_2002), Gly12Val substitution causes complete intracellular retention of the connexin and accumulates in large perinuclear vesicles. This dysfunction is accompanied by a significant decrease in its expression, suggesting that G12 is required for the maturation of connexin. Multiple laboratories via ClinVar also classify the variant as pathogenic/likely pathogenic. Considering all evidences, the variant has been classified as pathogenic. -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the GJB2 protein (p.Gly12Val). This variant is present in population databases (rs1801002, gnomAD 0.06%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 10982180, 19371219, 24158611, 25288386). ClinVar contains an entry for this variant (Variation ID: 21387). 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: 11032405, 12176036, 25625422). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	Common pathogenic variant in different population groups, predominantly reported in trans with the pathogenic c.35delG variant (Snoeckx et al., 2005); Published functional studies demonstrate this variant causes an intracellular trafficking defect with loss of intercellular transfer and transjunctional conductance (Garcia et al., 2005); Highly conserved residue in the intracellular amino-terminal domain, and variant is predicted to alter the flexibility of this region (Purnick et al., 2000); 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: 33096615, 30275481, 31160754, 16380907, 24158611, 25288386, 26043044, 26444186, 10982180, 11439000, 15365987, 19371219, 19887791, 19929407, 20083784, 20233142, 20668687, 21777984, 21962949, 26409293, 31370293, 25625422, 12176036, 11032405, 12172394, 17666888, 14691997, 11556849, 25388846) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2020	The GJB2 c.35G>T; p.Gly12Val variant (rs1801002) is a frequently reported pathogenic variant in Hispanic populations (see Purnick 2000, Putcha 2007, Rabionet 2000, Wu 2002). It has been found in a compound heterozygous state with the c.35delG variant and functional studies indicate the p.Gly12Val variant alters GJB2 protein function (D'Andrea 2012). This variant is reported in ClinVar (Variation ID: 21387) and is found in the general population with an overall allele frequency of 0.009% (21/244174 alleles) in the Genome Aggregation Database. Based on available information, we consider this variant to be pathogenic. REFERENCES D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. Purnick PE et al. Structure of the amino terminus of a gap junction protein. Arch Biochem Biophys. 2000 Sep 15;381(2):181-90. 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. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4. Wu BL et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002 Jul-Aug;4(4):279-88. -

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 filtering allele frequency of c.35G>T, p.Gly12Val variant is 0,038% (20/34584) of Latino alleles and 0,009% in all populations from gnomAD v2.1.1 database meeting PM2_Supporting criteria. This variant has been found in trans with several pathogenic variants in at least 10 patients with non-syndromic hearing loss among different populations applying to PM3_VerySrong criteria (PMID: 10982180, 11556849, 12172394, 12666888, 19371219, 20233142, 26043044, 26409293, 24158611). Computational analysis predicted the p.Gly12Val change to be damaging to the protein (REVEL=0.95; PP3). Functional studies in HeLa demonstrated that p.Gly12Val mutant was not able to form functional channels since there was a significantly reduce of dye (LuciferYellow) transfer meeting PS3_Moderate rule (PMID:12176036). Therefore, the c.35G>T variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2_Supporting, PM3_VeryStrong, PP3 and PS3_Moderate). -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 19, 2022

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2012

The Gly12Val variant in GJB2 has been reported in 4 individuals with hearing los s (Kenna 2001, D'Andrea P 2002, Kenna 2010, Rabionet 2000, Snoeckx 2005). At lea st two of these individuals were compound heterozygous. In addition, functional studies suggest that the Gly12Val variant may impact protein function (D'Andrea P 2002). In summary, this data suggests that this variant is likely pathogenic. -

GJB2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The GJB2 c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported in both the compound heterozygous and homozygous state in individuals with non-syndromic hearing loss (Rabionet et al. 2000. PubMed ID: 10982180; Buonfiglio et al. 2020. PubMed ID: 33096615; Figueroa-Ildefonso et al. 2019. PubMed ID: 31370293). A different missense change impacting the same amino acid (c.34G>T, p.Gly12Cys) has been reported in individuals with hearing loss (Internal Data, PreventionGenetics). In vitro functional studies demonstrate reduced protein expression and also showed cellular localization is entirely intracellular (D'Andrea et al. 2002. PubMed ID: 12176036).This variant is reported in 0.058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 3A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Sep 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;.;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-8.3

D;D;.

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.011

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.96

MutPred

0.93

Loss of disorder (P = 0.0289);Loss of disorder (P = 0.0289);Loss of disorder (P = 0.0289);

MVP

0.99

MPC

0.30

ClinPred

0.98

GERP RS

5.4

Varity_R

0.98

gMVP

0.95

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