rs1241595912

Positions:

• chrX-71224198-G-A
• chrX-71224198-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000166.6(GJB1):​c.491G>A​(p.Arg164Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U: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 14 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, 0.912
• PP5: Variant X-71224198-G-A is Pathogenic according to our data. Variant chrX-71224198-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 543920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224198-G-A is described in Lovd as [Pathogenic]. Variant chrX-71224198-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.491G>A	p.Arg164Gln	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.491G>A	p.Arg164Gln	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.491G>A	p.Arg164Gln	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.491G>A	p.Arg164Gln	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000580 AC: 1 AN: 172347 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 58611

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000716

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093603 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 1 AN XY: 359613

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000256

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GJB1: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2021	Published functional studies demonstrate a damaging effect, including reduced plasma membrane expression of GJB1 and GJ plaque formation combined with predominant cytoplasmic retention of GJB1, and impaired GJ permeability (Tsai et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10220155, 10737979, 12497641, 11571214, 23649551, 7580242, 9187667, 27098783, 18379723, 26454100, 9854984, 10923043, 17100997, 25025039, 20443038, 27544631, 15241803, 9361298, 14663027, 27844031, 15006706, 27025386, 27027447, 22243284, 31211173, 32022442, 31948496, 33726816) -

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

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2024	Variant summary: GJB1 c.491G>A (p.Arg164Gln) results in a conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-06 in 172347 control chromosomes (gnomAD). c.491G>A has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (e.g. Hsu_2019, Record_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37284795, 31211173). ClinVar contains an entry for this variant (Variation ID: 543920). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The p.R164Q variant (also known as c.491G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 491. The arginine at codon 164 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu V et al. Neuromuscul Disord, 1995 Jul;5:297-9; Bort S et al. Hum Genet, 1997 Jun;99:746-54; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401; Michaelidou K et al. Mol Genet Genomic Med, 2020 04;8:e1141; Li LX et al. Oncotarget, 2016 May;7:27655-64; Wang R et al. Clin Chim Acta, 2015 Dec;451:263-70; Braathen GJ. Acta Neurol Scand Suppl, 2012;:iv-22; Yoshihara T et al. Hum Mutat, 2000 Aug;16:177-8; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Choi BO et al. Hum Mutat, 2004 Aug;24:185-6; Dubourg O et al. Brain, 2001 Oct;124:1958-67; Huehne K et al. Hum Mutat, 2003 Jan;21:100; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Experimental studies have shown that this alteration causes mislocalization via cytoplasmic retention of GJB1 and significantly impairs Ca2+ signaling (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Peripheral neuropathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7580242, 9187667, 15006706, 27025386, 27027447). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 164 of the GJB1 protein (p.Arg164Gln). Experimental studies have shown that this missense change affects GJB1 function (PMID: 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 543920). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (PMID: 9187667, 10923043, 11571214, 12497641, 15241803, 22243284, 23106488, 25025039, 26454100, 27027447). This variant is present in population databases (no rsID available, gnomAD 0.007%). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;.;.;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D;.;D;.;D
REVEL	Pathogenic	0.85
Sift	Benign	0.077	T;.;T;.;T
Sift4G	Benign	0.25	T;.;T;.;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.72
MutPred		0.64		Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);
MVP		1.0
MPC		2.0
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1241595912; hg19: chrX-70444048; COSMIC: COSV62139915; COSMIC: COSV62139915;