rs80338946

chr13-20189243-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP3_Strong PP5_Strong

The NM_004004.6(GJB2):c.339T>G(p.Ser113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,236 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 Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:2 O:1
• Conservation: PhyloP100: -0.688

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 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_004004.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 13-20189243-A-C is Pathogenic according to our data. Variant chr13-20189243-A-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 21385.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.339T>G	p.Ser113Arg	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.339T>G	p.Ser113Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.339T>G	p.Ser113Arg	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.339T>G	p.Ser113Arg	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250234 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

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: 0.00000479 AC: 7 AN: 1461236 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000268

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 Cov.: 32

Alfa AF: 0.0000726 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GJB2 c.339T>G (p.Ser113Arg) missense variant has been reported in at least three studies in which it is found a total of four patients with an autosomal recessive form of nonsyndromic hearing loss, including in two in a compound heterozygous state and two in a heterozygous state where the zygosity of the variant is unknown (Kelly et al. 1998; Azaiez et al. 2004; Wang et al. 2013). The p.Ser113Arg variant was absent from 96 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies in Xenopus oocytes demonstrated that the variant resulted in only background levels of junctional conductance and did not induce the formation of homotypic junctional channels (Bruzzone et al. 2003). Structural modelling experiments showed that the variant is located at a conserved site (Fan et al. 2012). Based on the available evidence the p.Ser113Arg variant is classified as likely pathogenic for an autosomal recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Nonsyndromic genetic hearing loss Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 17, 2023	Variant summary: GJB2 c.339T>G (p.Ser113Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250234 control chromosomes. c.339T>G has been reported in the literature as a compound heterozygous genotype in at-least two individuals reportedly affected with features of non syndromic hearing loss (NSHL) and as a non-informative genotype (second allele not specified) in many non syndromic hearing loss cohorts (example, Kelley_1998, McGuirt_2002, Gardner_2006, Snoeckx_2005, Wang_2013). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Bruzzone_2003). The most pronounced variant effect results in loss of junctional conductance due to inability to form homotypic junctional channels. Two clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3 including the expert panel; Likely pathogenic, n=2) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jan 17, 2024	The c.339T>G variant in GJB2 is a missense variant predicted to cause substitution of serine by arginine at amino acid 113. The highest population minor allele frequency in gnomAD v4.0.0 is 0.02% (7/26136 alleles) in the Ashkenazi Jewish population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL provides a score of 0.553 which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function (PP3 and BP4 are not met). An in vitro functional study performed in Xenopus oocytes showed that variant junctional conductance for p.Ser113Arg was similar to water (negative control), indicating a loss of function impact on protein function (PS3_Moderate; PMID:12505163). The p.Ser113Arg variant has been reported in several probands with hearing loss, including 3 individuals with a second pathogenic variant without phase confirmation (1.5 points, PM3, PMID: 15365987, 11439000, 9529365, 16380907, 24078562). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PS3_Moderate, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 113 of the GJB2 protein (p.Ser113Arg). This variant is present in population databases (rs80338946, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 9529365, 12408072, 24078562). 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: 21385). 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 not expected to disrupt GJB2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	7.7
Dann	Benign	0.64
DEOGEN2	Uncertain	0.51	D;D;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.7e-12	A;A
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.88	N;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.32	T;T;.
Sift4G	Benign	0.46	T;T;.
Polyphen		0.025	B;B;B
Vest4		0.68
MutPred		0.78		Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);
MVP		0.81
MPC		0.044
ClinPred		0.046	T
GERP RS		-4.1
Varity_R		0.044
gMVP		0.77

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: rs80338946; hg19: chr13-20763382;