13-20189319-G-A

Variant names:

• chr13-20189319-G-A
• rs1555341945
• NM_004004.6:c.263C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004004.6(GJB2):​c.263C>T​(p.Ala88Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A88G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.94
• Publications: 1 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_004004.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 1A, ichthyosis, hystrix-like, with hearing loss, keratoderma hereditarium mutilans, hearing loss, autosomal recessive, Bart-Pumphrey syndrome, palmoplantar keratoderma-deafness syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss, KID syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 13-20189319-G-A is Pathogenic according to our data. Variant chr13-20189319-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1458348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.263C>T	p.Ala88Val	missense	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.263C>T	p.Ala88Val	missense	Exon 2 of 2	ENSP00000372299.4
	GJB2	ENST00000382844.2	TSL:6	c.263C>T	p.Ala88Val	missense	Exon 1 of 1	ENSP00000372295.1
	ENSG00000296095	ENST00000736390.1		n.232-3739C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Pathogenic:1

Jan 08, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Sep 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with autosomal dominant keratitis–ichthyosis–deafness (KID) syndrome (PMID: 20629838). In at least one individual the variant was observed to be de novo. This sequence change replaces alanine with valine at codon 88 of the GJB2 protein (p.Ala88Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23447037). For these reasons, this variant has been classified as Pathogenic.

Porokeratotic adnexal ostial nevus Pathogenic:1

Feb 07, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A GJB2 c.263C>T (p.Ala88Val) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in a germline state in numerous individuals with keratitis-ichthyosis-deafness (KID) syndrome (Koppelhus U et al., PMID: 20846357; Maarouf S et al., PMID: 39659087; Haruna K et al., PMID: 20629838; Lilly E et al., PMID: 30287322; López-Sundh AE et al., PMID: 36286624) and in four individuals as a somatic variant associated with porokeratotic adnexal ostial nevus (PAON) (Chang YH et al., PMID: 36478599; Zhao A et al., PMID: 38292003; Letertre O et al., PMID: 36734293). It has been reported in the ClinVar database as a pathogenic variant by two submitters (ClinVar ID: 1458348). Other variants at the same codon, p.Ala88Ser, p.Ala88Gly, p.Ala88Glu, and p.Ala88Pro, have been reported in individuals with various non-syndromic recessive conditions and are considered pathogenic (Posukh OL et al., PMID: 37892203). The GJB2 c.263C>T (p.Ala88Val) variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. It resides within a region, transmembrane domain 2, of GJB2 that is defined as a critical functional domain (Posukh OL et al., PMID: 37892203; Chang YH et al., PMID: 36478599). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on GJB2 function. In support of this prediction, functional studies show that the GJB2 c.263C>T (p.Ala88Val) variant significantly activates hemichannels and increased membrane current flow, resulting in accelerated cell death in low extracellular calcium concentrations (Bayraktar E et al., PMID: 38928300; Mhaske PV et al., PMID: 23447037; Yasarbas SS et al., PMID: 38827992). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Leon-Quintero FZ, et al., PMID: 39434542) and gene-specific practices from the ClinGen Criteria Specification Registry, the GJB2 c.263C>T (p.Ala88Val) variant is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Gain of sheet (P = 0.1208)
MVP		0.99
MPC		0.27
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.023	Neutral
Varity_R		0.81
gMVP		0.95
Mutation Taster		=7/93	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: rs1555341945; hg19: chr13-20763458;