rs1131691709

Positions:

• chr13-20189019-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387460893/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.97

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.563A>G	p.Lys188Arg	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.563A>G	p.Lys188Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.563A>G	p.Lys188Arg	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.563A>G	p.Lys188Arg	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 188 of the GJB2 protein (p.Lys188Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 17666888; external communication). 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: 429984). 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: 23967136). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2016	Variant summary: The c.563A>G variant involves the alteration of one of 5 invariant amino acid residues in the Connexin domain of GJB2 and 4/5 in silico tools predict a pathogenic outcome. The variant is absent from the large, broad ExAC control population and has been reported in the literature in two patients with hearing loss, at least one of whom also carried the known pathogenic GJB2 c.35delG variant in trans (Putcha_2007). Additionally, When expressed in HeLa cells, the K188R mutant failed to localize to cell membrane (Ambrosi_2013). Based on the highly conserved nature of the amino acid at position 563, despite limited clinical and functional data, this variant has been classified as a VUS - possibly pathogenic until additional evidence becomes available. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2017	The K188R variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic sensorineural hearing loss (Putcha et al., 2007). The K188R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K188R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (R184G, R184W, R184Q, R184P, T186M, T186K, V190D) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret K188R as a pathogenic variant. -

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Mar 28, 2024

The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.86		Loss of methylation at K188 (P = 0.0053);Loss of methylation at K188 (P = 0.0053);Loss of methylation at K188 (P = 0.0053);
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.99

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: rs1131691709; hg19: chr13-20763158;