NM_000166.6:c.556G>A

Variant names:

• chrX-71224263-G-A
• rs116840821
• NM_000166.6:c.556G>A

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_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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:1
• Conservation: PhyloP100: 10.0
• Publications: 20 publications found

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]

GJB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 23 uncertain in NM_000166.6
• 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 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• 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/Likely_pathogenic. ClinVar VariationId is 21086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.556G>A	p.Glu186Lys	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.556G>A	p.Glu186Lys	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.556G>A	p.Glu186Lys	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.556G>A	p.Glu186Lys	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:5 Other:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PS4_Moderate+PP4 -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.556G>A(p.Glu186Lys) in GJB1 gene has been reported previously in multiple individuals with Charcot-Marie-Tooth Neuropathy. Experimental studies have shown that this missense change affects GJB1 function (Tsai PC, et al., 2016, Bortolozzi M, 2018). -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP3 -

May 22, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1 PM2 PP3 PP5 -

not provided Pathogenic:3

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases Pathogenic:1

Aug 27, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). ClinVar contains an entry for this variant (Variation ID: 21086). 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 GJB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
LIST_S2	Pathogenic	1.0	.;.;.;.;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
PhyloP100		10
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
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs116840821; hg19: chrX-70444113; COSMIC: COSV107474183; COSMIC: COSV107474183;