NM_004004.6:c.250G>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_004004.6(GJB2):c.250G>C(p.Val84Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

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 14 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 13-20189332-C-G is Pathogenic according to our data. Variant chr13-20189332-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189332-C-G is described in Lovd as [Likely_pathogenic]. Variant chr13-20189332-C-G is described in Lovd as [Pathogenic]. Variant chr13-20189332-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6 link	c.250G>C	p.Val84Leu	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 link	c.250G>C	p.Val84Leu	missense_variant	Exon 2 of 2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 link	c.250G>C	p.Val84Leu	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 link	c.250G>C	p.Val84Leu	missense_variant	Exon 1 of 1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251338

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000387

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:8

Nov 13, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GJB2 c.250G>C (p.Val84Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The Val84 is proposed to be at the membrane-spanning segments M2/M3 helix interface of the GJB2 protein (Ambrosi_2010). This variant was found in 8/121696 control chromosomes from ExAC at a frequency of 0.0000657, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is widely reported as a pathogenic variant in literature and is found in ARNSHL patients in homozygous as well as in compound heterozygous state with other known pathogenic variants, including evidence of cosegregation with disease (Kelley_1998, Azaiez_2004, Snoeckx_2005, Zoll_2002, Dalamon_2013, Dahl_2013). Multiple functional studies show that although the V84L mutant channels are able to make gap junctions in mammalian and insect cells, stable in detergent solution and able to allow passage of simple ions (such as LY), they do not allow permeability for molecules larger than simple ions (such as propidium iodide) and reduce permeability to the Ca2+-mobilizing messenger inositol 1,4,5-trisphosphate (Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense variant at this residue p.V84M has been classified as pathogenic by our lab and others in ClinVar. Taken together, this variant is classified as Pathogenic. -

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 02, 2023

Integrating Genomics into Medicine, Frazer Institute, University Of Queensland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 both deafness and skin conditions (OMIM). 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 valine to leucine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). An alternative nucleotide change to adenine resulting in the same protein change is also present in gnomAD (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Val84Met) has been reported multiple times as pathogenic in ClinVar. (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The same nucleotide change, as well as the alternative change to adenine, have been reported in compound heterozygote and homozygote individuals with deafness (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 29, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017032 /PMID: 9529365). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11556849, 16380907). Different missense changes at the same codon (p.Val84Ala, p.Val84Met) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017036, VCV002137459 /PMID: 12325027). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 18, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Jul 12, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 17032). 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. -

Dec 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on biochemical permeability, while ionic coupling is intact (PMID: 16217030); 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: 17426645, 24158611, 23555729, 15365987, 25087612, 25388846, 15592461, 16380907, 14985372, 12562518, 12505163, 20441744, 9529365, 17666888, 12189487, 31160754, 33096615, 31589614, 36048236, 34308104, 31331740, 11556849, 16217030) -

May 26, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in impaired permeability to larger molecules, such as inositol 1,4,5-trisphosphate (PMID: 15592461, 16217030). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -

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.250G>C, p.Val84Leu has a filtering allele frequency of 0.00395% in Latino population from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) meeting PM2 criteria. Computational analysis predicted a pathogenic effect of the variant to the protein (REVELscore=0.947) applying to PP3 rule. This variant was identified in trans with at least 5 known pathogenic variants meeting PM3_VeryStrong criteria (PMID: 24158611, 95239365, 11556849,12172394, 12189487,12497637, 14985372, 15365987, 17041943). The p.Val84Leu change in trans with a pathogenic variant segregated in two affected siblings in a family case. (PP1_Supporting; PMID: 95239365). Dye transfer and electrical coupling assays demonstrated that the variant do not impact the protein function (PMID: 12505163, 12562518, 16217030). However, some assays showed a reduce permeability to IP3 and intracellular exchange of large molecules (PMID: 12505163, 16217030), and therefore this evidence was not counted. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP3, PM3_VeryStrong and PP1_Supporting). -

Hearing impairment

Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Jun 22, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val84Leu variant in GJB2 has been reported in 7 individuals with hearing l oss, 6 of whom were compound heterozygous for a second pathogenic variant and 1 of whom was homozygous for the variant, and segregated in 3 affected siblings wi th hearing loss (Cryns 2004, Kelley 1998, Kenna 2001, LMM Unpublished data). Thi s variant was identified in 4/33580 Latino chromosomes; however, this frequency is low enough to be consistent with a recessive carrier frequency. Functional st udies indicate that the Val84Leu variant compromises connexin 26 protein functio n (Beltramello 2005). In summary, this variant meets criteria to be classified a s pathogenic for autosomal recessive hearing loss based on the previously report ed individuals, segregation data, and low frequency in the general population. -

GJB2-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a compound heterozygous or homozygous variant in individuals with congenital hearing impairment (PMID: 16380907, 26346709, 24013081, 19235794, 11556849, 12172394, 12189487, 12497637, 15365987). Functional studies have shown that this missense change affects biochemical permeability and intercellular transport of large molecules (PMID: 12505163, 12562518, 15592461, 20441744, 16217030). The c.250G>C (p.Val84Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (9/251338) and is absent in the homozygous state, thus is presumed to be rare. In silico analyses predict a deleterious effect of the c.250G>C (p.Val84Leu) variant on protein function. Based on the available evidence, the c.250G>C (p.Val84Leu) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.38

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

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;D;.

REVEL

Pathogenic

0.95

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

0.88

GERP RS

5.3

Varity_R

0.90

gMVP

0.96

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