rs116840821

chrX-71224263-G-AchrX-71224263-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):c.556G>A(p.Glu186Lys) 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. E186V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 10.0

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. 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 cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-71224263-G-A is Pathogenic according to our data. Variant chrX-71224263-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224263-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.556G>A	p.Glu186Lys	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.556G>A	p.Glu186Lys	missense_variant	2/2
GJB1	XM_011530907.3	c.556G>A	p.Glu186Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.556G>A	p.Glu186Lys	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 22243284, 9364054, 10848620, 8266101, 27844031, 31211173, 10737979, 32376792, 12542510, 7946361) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly compromised plasma membrane localization and failed to form functional channels (PMID: 27844031, 7946361, 9364054). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 24, 2023	PS3, PS4, PM2, PP3 -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Liu X et al. Front Neurol, 2020 Jul;11:690; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Takashima H et al. Acta Neurol Scand, 2003 Jan;107:31-7; Dubourg O et al. Brain, 2001 Oct;124:1958-67). In addition, this mutation has been reported to segregate with CMTX1 in one family (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35). Functional studies indicate that the E186K alteration impairs localization and channel function (Matsuyama W et al. J Hum Genet, 2001;46:307-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Vanslyke JK et al. Mol Biol Cell, 2009 May;20:2451-63; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). 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 GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 21086). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the GJB1 protein (p.Glu186Lys). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;D
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;.;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.97
MutPred		0.91		Gain of methylation at E186 (P = 0.0046);Gain of methylation at E186 (P = 0.0046);Gain of methylation at E186 (P = 0.0046);Gain of methylation at E186 (P = 0.0046);Gain of methylation at E186 (P = 0.0046);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.98
gMVP		1.0

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: rs116840821; hg19: chrX-70444113;