13-20188998-A-G

Variant names:

• chr13-20188998-A-G
• rs1378679640
• NM_004004.6:c.584T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PM5 PP3 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.584T>C is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 195 (p.Met195Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0022% (4/60018, CI 95%) in the Admixed American population (PM2_Supporting). The c.584T>C variant has been detected in trans with c.35delG in one individual with moderate-severe hearing loss (PMID:19235794). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). Analysis in Hela cells demonstrated that the CX26-p.Met195Thr protein formed a gap junction but with significantly decreased dye transfer. Additionally, electrophysiological characterization of the mutant in Xenopus oocytes resulted in a completely non-functional channel (PS3_Moderate; PMID:23967136). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PP3, PM3, PM5, PS3_Moderate; Version 2; 5/15/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387460849/MONDO:0019497/005

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 9.27
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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 rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.584T>C	p.Met195Thr	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.584T>C	p.Met195Thr	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.584T>C	p.Met195Thr	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.584T>C	p.Met195Thr	missense_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3418T>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251352 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000684 AC: 10 AN: 1461662 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the GJB2 protein (p.Met195Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 19235794, 20233142). ClinVar contains an entry for this variant (Variation ID: 438620). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20497192, 24013081, 30146550, 33597575). 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. -

Dec 26, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss Pathogenic:1

May 15, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.584T>C is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 195 (p.Met195Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0022% (4/60018, CI 95%) in the Admixed American population (PM2_Supporting). The c.584T>C variant has been detected in trans with c.35delG in one individual with moderate-severe hearing loss (PMID: 19235794). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). Analysis in Hela cells demonstrated that the CX26-p.Met195Thr protein formed a gap junction but with significantly decreased dye transfer. Additionally, electrophysiological characterization of the mutant in Xenopus oocytes resulted in a completely non-functional channel (PS3_Moderate; PMID: 23967136). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PP3, PM3, PM5, PS3_Moderate; Version 2; 5/15/24). -

not specified Uncertain:1

Sep 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB2 c.584T>C (p.Met195Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. This alters a highly conserved residue in which other missense variants have been found in association with hearing loss (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251352 control chromosomes (gnomAD). c.584T>C has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss without strong evidence of causality (Lee_2009, Chinetti_2010). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. At least one publication reports experimental evidence evaluating an impact on protein function, funding no impact on gap junction formation or stability but substantially reduced function (Ambrosi_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19235794, 23967136, 20233142). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:1

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.025	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.74		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.95
MPC		0.30
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs1378679640; hg19: chr13-20763137;