chr13-20189472-A-G

Position:

chr13-20189472-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5_StrongPM3PP3

This summary comes from the ClinGen Evidence Repository: The c.1101T>C variant in GJB2 is a missense variant predicted to cause substitution of valine by alanine at amino acid 37 (p.Val37Ala). The highest population filtering allele frequency in gnomAD v4 is 0.03% (25/74924 alleles) in the African American population (PM2_Supporting, BA1, and BS1 not met). This variant has been identified in 11 heterozygous individuals who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987,GeneDx Internal Data, Invitae Internal Data), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (1 point, PM3; Partners LMM internal data SCV000967620.2, GeneDx Internal Data, Invitae Internal Data). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). Two different pathogenic missense variants (p.Val37Ile and p.Val37Phe) have been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5_Strong, p.Val37Ile ClinVar Variation ID 17023, PMID 31160754; p.Val37Phe ClinVar Variation ID:179256 PMID:37108562). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3, PM5_Strong, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA6904317/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GJB2
NM_004004.6 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 9.26

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 Likely_pathogenic. Variant got 7 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6 linkuse as main transcript	c.110T>C	p.Val37Ala	missense_variant	2/2	ENST00000382848.5	NP_003995.2	P29033H9U1J4
GJB2	XM_011535049.3 linkuse as main transcript	c.110T>C	p.Val37Ala	missense_variant	2/2		XP_011533351.1	P29033H9U1J4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5 linkuse as main transcript	c.110T>C	p.Val37Ala	missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4		P29033
GJB2	ENST00000382844.2 linkuse as main transcript	c.110T>C	p.Val37Ala	missense_variant	1/1	6		ENSP00000372295.1		P29033

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000757

AC:

AN:

250894

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000289

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000224

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:

0.00000810

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000138

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000458

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

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2021	Variant summary: GJB2 c.110T>C (p.Val37Ala) results in a non-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 7.6e-05 in 250894 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (7.6e-05 vs 0.025), allowing no conclusion about variant significance. c110T>C has been reported in the literature in individuals affected with congenital deafness (Azaiez_2004), non-syndromic sensorineural hearing loss (Lipan_2011), moderate hearing loss (Putcha_2007) and sensorineural hearing loss (Gruber_2016). A second variant in the GJB2 gene was not identified in the individuals reported in these studies, however the variant was reported to co-occur with a GJB6 variant (c.631T>G, p.C211G) of unknown pathogenicity in one patient (Putcha_2007). In addition, one Clinvar submitter reports that this variant has been detected in trans with a second pathogenic GJB2 variant in an individual with hearing loss tested at their facility. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 09, 2020	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ala). This variant is present in population databases (rs141774369, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15365987, 17666888). ClinVar contains an entry for this variant (Variation ID: 449490). 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%. This variant disrupts the p.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15365987, 17666888). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2024	Observed heterozygous with no other GJB2 variants in patients with hearing loss in published literature (PMID: 15365987, 17666888, 21287563); 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: 25388846, 21287563, 25087612, 17666888, 27466889, 15365987, 36048236) -

Nonsyndromic genetic hearing loss

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Apr 22, 2024

The c.1101T>C variant in GJB2 is a missense variant predicted to cause substitution of valine by alanine at amino acid 37 (p.Val37Ala). The highest population filtering allele frequency in gnomAD v4 is 0.03% (25/74924 alleles) in the African American population (PM2_Supporting, BA1, and BS1 not met). This variant has been identified in 11 heterozygous individuals who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987,GeneDx Internal Data, Invitae Internal Data), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (1 point, PM3; Partners LMM internal data SCV000967620.2, GeneDx Internal Data, Invitae Internal Data). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). Two different pathogenic missense variants (p.Val37Ile and p.Val37Phe) have been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5_Strong, p.Val37Ile ClinVar Variation ID 17023, PMID 31160754; p.Val37Phe ClinVar Variation ID:179256 PMID: 37108562). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3, PM5_Strong, PP3. (Hearing Loss VCEP specifications version 2; 4/22/2024) -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2019

The p.Val37Ala variant in GJB2 has been previously reported in several individuals with hearing loss in whom a second GJB2 variant was not identified. However, this variant has also been identified by our laboratory in one individual with hearing loss who carried a second pathogenic GJB2 variant. This variant has been identified in 0.036% (13/35428) of Latino chromosomes and in 0.36% (9/24968) of African by gnomAD (http://gnomad.broadinstitute.org), which are low enough to be consistent with recessive carrier frequencies. Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, a pathogenic (p.Val37Ile) and likely pathogenic (p.Val37Phe) at the same amino acid residue have been previously reported in individuals with hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3, PM5, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.76

D;D;D

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

.;.;T

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Pathogenic

0.68

Sift

Benign

0.20

T;T;.

Sift4G

Benign

0.58

T;T;.

Polyphen

1.0

D;D;D

Vest4

0.94

MVP

0.84

MPC

0.27

ClinPred

0.15

GERP RS

5.2

Varity_R

0.51

gMVP

0.91

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