rs756928158

Positions:

• chrX-71223978-G-A
• chrX-71223978-G-C

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.271G>A​(p.Val91Met) 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-71223978-G-A is Pathogenic according to our data. Variant chrX-71223978-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 195025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223978-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.271G>A	p.Val91Met	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.271G>A	p.Val91Met	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.271G>A	p.Val91Met	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.271G>A	p.Val91Met	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Jun 10, 2022	ACMG categories: PS3,PM1,PM2,PP3,PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 13, 2019	The GJB1 c.271G>A (p.Val91Met) variant is a missense variant that has been reported in a heterozygous state in at least eight individuals with Charcot-Marie-Tooth neuropathy (Bissar-Tadmouri et al. 2000; Dobourg et al. 2001; Michelle et al. 2009; Arthur-Farraj et al. 2012; Tsai et al. 2016; Hong et al. 2017). Affected individuals presented with motor neuropathy, areflexia, ataxia, paresthesia of the feet, numbness and/or weakness of lower limbs, and sensorineural hearing loss in at least one affected individual. Age of onset was variable, but generally occurred in the first or second decade. The p.Val91Met variant was absent from 50 control individuals (Dobourg et al. 2001) and is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Functional studies in HeLa cells showed decreased expression of the p.Val91Met variant protein in the plasma membrane compared to controls (Tsai et al. 2016). In addition, the variant protein was mainly localized to the cytoplasm and showed fewer gap junction plaques at the intercellular boundaries compared to wild-type. Additional tests were conducted in HEK293T cells where Ca2+ signaling propagation was evaluated. Impaired gap junction permeability was observed and the onset-to-peak duration of the signal was longer in cells expressing the p.Val91Met variant compared to those expressing wild-type protein (Tsai et al. 2016). The p.Val91Met variant is located in the second transmembrane domain which is suggested to be important for protein conformation. Based on the collective evidence, the p.Val91Met variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 91 of the GJB1 protein (p.Val91Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMTX (PMID: 11140841, 11571214, 22464564, 27027447, 27844031, 28097225). ClinVar contains an entry for this variant (Variation ID: 195025). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;.;.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;.;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;.;D;.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;D;.;.;D
Sift4G	Uncertain	0.0040	D;.;D;.;.;D
Polyphen		1.0	D;D;D;D;.;D
Vest4		0.76
MutPred		0.92		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.98

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: rs756928158; hg19: chrX-70443828;