rs786204123

Positions:

• chrX-71224132-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.425G>A​(p.Arg142Gln) 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. R142W) has been classified as 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 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 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71224131-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-71224132-G-A is Pathogenic according to our data. Variant chrX-71224132-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224132-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.425G>A	p.Arg142Gln	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.425G>A	p.Arg142Gln	missense_variant	2/2
GJB1	XM_011530907.3	c.425G>A	p.Arg142Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.425G>A	p.Arg142Gln	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2019	The GJB1 c.425G>A; p.Arg142Gln variant (rs786204123) is reported in the literature in several individuals and families affected with X-linked Charcot-Marie-Tooth (CMT) disease (Dubourg 2001, Ikegami 1998, Stojkovic 1999). In one family, which also exhibited sensorineural deafness, this variant was found in at least six affected individuals and was absent from two unaffected relatives, although it was also found in two individuals without symptoms who may have been too young to manifest with disease (Stojkovic 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 142 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Arg142Gly, p.Arg142Trp) have been reported in individuals with CMT and are considered disease-causing (Bergoffen 1993, Lorefice 2017, Yuan 2018). Based on available information, the p.Arg142Gln variant is considered to be likely pathogenic. References: Bergoffen J et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. 1993 Dec 24;262(5142):2039-42. Dubourg O et al. Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain. 2001 Oct;124(Pt 10):1958-67. Ikegami T et al. Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1. Am J Med Genet. 1998 Dec 4;80(4):352-5. Lorefice L et al. Charcot-Marie-Tooth disease: genetic subtypes in the Sardinian population. Neurol Sci. 2017 Jun;38(6):1019-1025. Stojkovic T et al. Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q). Neurology. 1999 Mar 23;52(5):1010-4. Yuan JH et al. Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1. Eur J Neurol. 2018 Dec;25(12):1454-1461. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2022

The c.425G>A (p.R142Q) alteration is located in exon 2 (coding exon 1) of the GJB1 gene. This alteration results from a G to A substitution at nucleotide position 425, causing the arginine (R) at amino acid position 142 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple unrelated individuals in the hemizygous and heterozygous state in mildly affected females with features consistent with Charcot-Marie-Tooth disease (Dubourg, 2001; Kim, 2012; Milley, 2016; Lu, 2017; Chen, 2019; Hardy, 2019; Tian, 2021; Volodarsky, 2021). In addition, this alteration was shown to segregate with disease in multiple individuals from two families who have clinical features consistent with Charcot-Marie-Tooth disease (Stojkovic, 1999; Liang, 2019). This amino acid position is highly conserved in available vertebrate species. Functional assays demonstrate reduced junctional conductance compared to controls in vitro (Abrams, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 142 of the GJB1 protein (p.Arg142Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT1X (PMID: 9361298, 10102421, 11571214). ClinVar contains an entry for this variant (Variation ID: 188174). 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%. This variant disrupts the p.Arg142 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8004109, 9361298, 10207904, 10848620). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2022

Previously reported many times in association with CMTX1; some patients with R142Q also had deafness and central nervous system symptoms (Stojkovic et al., 1999; Dubourg et al., 2001; Kulkarni et al., 2015; Lu et al., 2017; Bone et al., 1997).; Published functional studies demonstrate that the R142Q variant alters the formation and structure of gap junction plaques (Abrams et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12542510, 30042657, 9856562, 28071741, 17603245, 11571214, 25745327, 28469099, 19259128, 27544631, 21291455, 28448691, 9361298, 29998508, 32376792, 31323543, 31220874, 31842800, 32903794, 30952033, 33314704, 10102421) -

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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	N;.;N;.;N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.0030	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.88
MutPred		0.95		Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.88
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: rs786204123; hg19: chrX-70443982;