rs786204756

Positions:

chr13-20188986-G-A

Variant summary

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

The NM_004004.6(GJB2):c.596C>T(p.Ser199Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,868 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. S199A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.94

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_004004.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-20188987-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2087433.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 13-20188986-G-A is Pathogenic according to our data. Variant chr13-20188986-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20188986-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.596C>T	p.Ser199Phe	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3 linkuse as main transcript	c.596C>T	p.Ser199Phe	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.596C>T	p.Ser199Phe	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2 linkuse as main transcript	c.596C>T	p.Ser199Phe	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000119

AC:

AN:

251284

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00000479

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Published functional studies demonstrate impaired membrane targeting, aberrant cellular localization, and intracellular aggregation (Xiao et al., 2011; Ambrosi et al., 2013); 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: 25262649, 10376574, 25388846, 11102979, 15365987, 12408072, 20863150, 25999548, 21738759, 19027181, 25085072, 29311818, 31160754, 31589614, 33297549, 23967136) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 199 of the GJB2 protein (p.Ser199Phe). This variant is present in population databases (rs771748289, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 15365987, 19027181). ClinVar contains an entry for this variant (Variation ID: 189183). 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: 20863150, 23967136). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2019	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in multiple families, but using affected individuals only. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	Variant summary: The GJB2 c.596C>T (p.Ser199Phe) variant involves the alteration of a conserved nucleotide and Ser199 is located in cytoplasmic region (UniProt). 5/5 in silico tools predict damaging outcome for this variant. This variant was found in 1/120100 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been reported in several patients with non-syndromic hearing loss in homozygous as well as in compound heterozygous state with c.35delT and GJB6 deletion and was found to be the most common pathogenic variant in Columbia (Green_1999, Prasad_2000, Azaiez_2004, Snoeckx_2005, Putcha_2007, Tamayo_2009, Rodriguez-Paris_2011). Two independent functional studies showed that this variant leads to defective trafficking (Xiao_2011, Ambrosi_2013). One clinical diagnostic laboratory in ClinVar has classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 17, 2015	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

GJB2 NM_004004.5 exon 2 p.Ser199Phe (c.596C>T): This variant has been reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with autosomal recessive nonsyndromic hearing loss (Green 1999 PMID:10376574, Tamayo 2009 PMID:19027181, Rodriguez-Paris 2011 PMID:21738759). This variant is present in 0.006% (2/34580) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/13-20763125-G-A) and is present in ClinVar (Variation ID:189183). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vitro functional studies in HeLa cells transfected with S199F have shown a deleterious effect of this variant (Ambrosi 2013 PMID:23967136; Xiao 2011 PMID:20863150). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -

GJB2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2023

The GJB2 c.596C>T variant is predicted to result in the amino acid substitution p.Ser199Phe. This variant has been reported as pathogenic for autosomal recessive hearing loss (Green et al 1999. PubMed ID: 10376574; Table S4, Shearer et al. 2014. PubMed ID: 25262649; 2015. PubMed ID: 25388846; García-García et al. 2020. PubMed ID: 33297549; Rodriguez-Paris et al. 2011. PubMed ID: 21738759), and functional experiments have demonstrated aberrant GJB2 protein localization to the cytoplasm (Ambrosi et al. 2013. PubMed ID: 23967136). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763125-G-A). This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2016

The p.Ser199Phe variant in GJB2 is a common pathogenic variant in the Colombian population, where it has been reported in the homozygous state in 11 individuals with hearing loss (Tamayo 2009). It has also been reported in >15 additional in dividuals with hearing loss who carried a second pathogenic GJB2 variant affecti ng the other allele (Green 1999, Tamayo 2009, Rodriguez-Paris 2011). In vitro fu nctional studies provide some evidence that the p.Ser199Phe variant may impact p rotein function (Xiao 2011, Ambrosi 2013). However, these types of assays may no t accurately represent biological function. This variant has been identified in 1/120100 total chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs771748289). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rec essive carrier frequency. In summary, this variant meets criteria to be classifi ed as pathogenic for hearing loss in an autosomal recessive manner. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.1

D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;D

Vest4

0.98

MutPred

0.78

Loss of glycosylation at S199 (P = 0.0501);Loss of glycosylation at S199 (P = 0.0501);Loss of glycosylation at S199 (P = 0.0501);

MVP

0.99

MPC

0.29

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.98

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