rs111033295

chr13-20189217-T-Achr13-20189217-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_004004.6(GJB2):c.365A>T(p.Lys122Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,712 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.04

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_004004.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 13-20189217-T-A is Pathogenic according to our data. Variant chr13-20189217-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.365A>T	p.Lys122Ile	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.365A>T	p.Lys122Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.365A>T	p.Lys122Ile	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.365A>T	p.Lys122Ile	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000599 AC: 15 AN: 250324 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

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: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461476 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000335

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: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.0000264

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 122 of the GJB2 protein (p.Lys122Ile). This variant is present in population databases (rs111033295, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal recessive nonsyndromic deafness (PMID: 10376574, 22925408, 31160754; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44742). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	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: 26275501, 25447126, 12865758, 10751669, 10376574, 25388846, 16125251, 22925408, 32003480, 17041943, 15365987, 11102979, 19235794, 17666888, 19081147, 18368581, 16222667, 12408072, 18776652, 10980526, 12067629, 26444186, 12457340, 30708180, 10704187, 31160754) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 29, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2016	Variant summary: The GJB2 c.365A>T (p.Lys122Ile) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 6/121646 control chromosomes at a frequency of 0.0000493, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been identified in compound heterozygous state in patients with non-syndromic hearing loss, and is considered pathogenic in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 25, 2018	This variant was reported as pathogenic in the compound heterozygous state in patients with Deafness, autosomal recessive 1 (PMID: 25388846 and 10376574). This variant has also been previously reported as a heterozygous change in patients with hearing loss of an unspecified inheritance pattern (PMID: 12865758, 16222667, 17041943, 18776652). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0053% (13/245106) and thus is presumed to be rare. The c.365A>T (p.Lys122Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.365A>T (p.Lys122Ile) variant is classified as pathogenic. -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 02, 2019

The GJB2 c.365A>T; p.Lys122Ile (rs111033295) is reported in the literature in multiple individuals with hearing loss (de la Luz Arenas-Sordo 2012, Green 1999, Lee 2009, Naghavi 2008, Pandya 2007, Prasad 2000, Putcha 2007, Tang 2006), and it has been previously identified by our laboratory in several patients who were referred for hearing loss. Several affected individuals were found to carry an additional pathogenic variant (de la Luz Arenas-Sordo 2012, Lee 2009, Putcha 2007). The p.Lys122Ile variant is classified as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variant ID: 44742) and it is found in the Latino population with an overall allele frequency of 0.04% (15/34582 alleles) in the Genome Aggregation Database. The lysine at codon 122 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on the available information, the p.Lys122Ile variant is classified as likely pathogenic. References: de la Luz Arenas-Sordo et al. Unique spectrum of GJB2 mutations in Mexico. Int J Pediatr Otorhinolaryngol. 2012 Nov;76(11):1678-80. doi: 10.1016/j.ijporl.2012.08.005. Epub 2012 Aug 24. Green et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Lee et al. Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. Laryngoscope. 2009 Mar;119(3):554-8. Naghavi et al. GJB2 mutations in Baluchi population. J Genet. 2008 Aug;87(2):195-7. Pandya et al. Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med. 2003 Jul-Aug;5(4):295-303. Prasad et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha 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. Tang et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 19, 2013

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.365A>T (p.K122I) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from an A to T substitution at nucleotide position 365, causing the lysine (K) at amino acid position 122 to be replaced by an isoleucine (I)._x000D_ _x000D_ Based on the available evidence, the GJB2 c.365A>T (p.K122I) alteration is classified as pathogenic for autosomal recessive GJB2-related nonsyndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related nonsyndromic hearing loss and GJB2-related syndromic hearing loss with ectodermal involvement is unclear. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (15/250324) total alleles studied. The highest observed frequency was 0.043% (15/34582) of Latino alleles. This variant has been identified with a second GJB2 variant in multiple individuals with hearing loss (Green, 1999; Putcha, 2007; Lee, 2009; de la Luz Arenas-Sordo, 2012; Shen, 2019). This variant has also been reported in the absence of a second GJB2 alteration in multiple heterozygous individuals with hearing loss (Azaiez, 2004; Cheng, 2005; Tang, 2006; Naghavi, 2008; Tayoun, 2016). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 13, 2012

The Lys122Ile variant in GJB2 has been reported in 18 probands with hearing loss and was absent from over 400 control samples (Green 1999, Pandya 2003, Tang 200 6, Naghavi 2008). Therefore, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.85
Sift	Benign	0.087	T;T;.
Sift4G	Uncertain	0.043	D;D;.
Polyphen		0.96	D;D;D
Vest4		0.46
MutPred		0.79		Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);Loss of solvent accessibility (P = 0.0017);
MVP		0.99
MPC		0.31
ClinPred		0.79	D
GERP RS		4.3
Varity_R		0.79
gMVP		0.92

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: rs111033295; hg19: chr13-20763356;