rs80338944

Positions:

• chr13-20189351-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004004.6(GJB2):​c.231G>A​(p.Trp77*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,054 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: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GJB2 NM_004004.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 48 pathogenic variants in the truncated region.
• PP5: Variant 13-20189351-C-T is Pathogenic according to our data. Variant chr13-20189351-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189351-C-T is described in Lovd as [Pathogenic]. Variant chr13-20189351-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.231G>A	p.Trp77*	stop_gained	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.231G>A	p.Trp77*	stop_gained	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.231G>A	p.Trp77*	stop_gained	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.231G>A	p.Trp77*	stop_gained	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251384 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461840 Hom.: 0 Cov.: 33 AF XY: 0.000165 AC XY: 120 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000256 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:6 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 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 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) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (35 heterozygotes, 0 homozygotes). (SP) 0701 - Other protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least five pathogenic protein truncating variants downstream of this variant (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories and is a common pathogenic variant in the Pakistani population (ClinVar; PMID: 30303587). This variant has also been classified as pathogenic in the Deafness Variation Database. (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 19, 2018	Variant summary: GJB2 c.231G>A (p.Trp77X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 246196 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00015 vs 0.025). c.231G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in homozygous and compound heterozygous state (e.g. Kelsell 1997, Santos 2005, Mani 2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 04, 2023	A heterozygous nonsense variant in exon 2 of the GJB2 gene that results in a stop codon and premature truncation of the protein at codon 77 (p.Trp77Ter) was detected. This variant has not been reported in 1000 genomes database and has a minor allele frequency of 0.004%, 0.01%, 0.0008% in the, gnomAD (v3.1), gnomdAD (v2), topmed and databases, respectively. The in silico prediction of the variant is damaging by MuttaionTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. 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: 33187236). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 33187236). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017001 / PMID: 9139825 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2023	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features of nonsyndromic hearing loss and deafness and is considered one of the most common causes of deafness among individuals of South Asian ancestry (PMID: 25636251). This variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic, and segregates with disease in multiple families. -
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	Revvity Omics, Revvity	Feb 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Trp77*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338944, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 9139825, 24840842, 25636251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17001). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Lys112Glufs*2) have been determined to be pathogenic (PMID: 9529365, 23141775). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22975760, 24949729, 19465004, 25087612, 25636251, 24840842, 9139825, 18941476, 29921236, 29542069, 29086887, 30168495, 20086291, 18983339, 31980526, 33614373) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Fulgent Genetics, Fulgent Genetics

Apr 24, 2024

- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

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

Oct 31, 2018

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 22, 2017

The p.Trp77X variant in GJB2 has been reported in several individuals with heari ng loss who were either homozygous or compound heterozygous with a second pathog enic variant in GJB2 (Kelsell 1997, Scott 1998, Rickard 2001, Santos 2005, Mani 2008, Padma 2009, Shafique 2014, LMM data). It has also been identified in 35/30 782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs80338944), which is consistent with the carrie r frequency for recessive hearing loss in the general population. This nonsense variant leads to a premature termination codon at position 77, which is predicte d to lead to a truncated protein. Loss of function of the GJB2 gene is an establ ished disease mechanism in autosomal recessive nonsyndromic hearing loss. In add ition, another nonsense variant at an adjacent nucleotide position (c.230G>A) re sulting in the same amino acid change has also been reported in many individuals with hearing loss (Hwa 2003, Bazazzagedan 2012, Huang 2015). Several individual s have been reported with the p.Trp77X variant; however, the nucleotide change w as not described (Cheng 2005, Bajaj 2008, Bhalla 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing l oss based upon the predicted impact of the variant, and homozygosity or compound heterozygosity in multiple affected individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.92
GERP RS		5.3

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

Other links and lift over

dbSNP: rs80338944; hg19: chr13-20763490;