rs116840815

Variant names:

• chrX-71223750-C-T
• rs116840815
• NM_000166.6:c.43C>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.43C>T​(p.Arg15Trp) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 3.18

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, 0.971
• PP5: Variant X-71223750-C-T is Pathogenic according to our data. Variant chrX-71223750-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223750-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.43C>T	p.Arg15Trp	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.43C>T	p.Arg15Trp	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	XM_011530907.3	c.43C>T	p.Arg15Trp	missense_variant	Exon 2 of 2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.43C>T	p.Arg15Trp	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 (MIM#1302800) (PMID 30042657). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance with some females remaining asymptomatic (GeneReviews).(I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The GJB1 c.44G>A; p.(Arg15Gln) and c.44G>C; p.(Arg15Pro) variants have been previously reported in multiple individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB1 c.43C>T; p.Arg15Trp variant (rs116840815; ClinVar Variation ID: 217169) is reported in the literature in multiple individuals affected with clinical features consistent with Charcot-Marie-Tooth disease (Nam 2016, Nelis 1996, Nguyen-Le 2022, Yalcouye 2022). Functional analyses of the variant protein show impaired conductance similar to complete knockout of GJB1 (Abrams 2001). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.44G>A; p.Arg15Gln; c.44G>T; p.Arg15Leu) have been reported in individuals with Charcot-Marie-Tooth disease and are considered pathogenic (Fairweather 1994 and Lu 2017). Based on available information, the p.Arg15Trp variant is considered to be pathogenic. References: Abrams CK et al. Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res. 2001 May 4;900(1):9-25. PMID: 11325342 Fairweather N et al. Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Mol Genet. 1994 Jan;3(1):29-34. PMID: 8162049. Lu YY et al. Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. Chin Med J (Engl). 2017 May 5;130(9):1049-1054PMID: 28469099 Nam SH et al. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. Mol Cells. 2016 May 31;39(5):382-8. PMID: 27025386 Nelis E et al. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet. 1996;4(1):25-33. PMID: 8800924. Nguyen-Le TH et al. Genotype-phenotype characteristics of Vietnamese patients diagnosed with Charcot-Marie-Tooth disease. Brain Behav. 2022 Sep;12(9):e2744. PMID: 35938991 Yalcouye A et al. GJB1 variants in Charcot-Marie-Tooth disease X-linked type 1 in Mali. J Peripher Nerv Syst. 2022 Jun;27(2):113-119. PMID: 35383424. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:2

Feb 26, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the published literature in association with GJB1-related Charcot-Marie-Tooth disease (PMID: 9328258); Published functional studies demonstrate a damaging effect on channel function (PMID: 11325342, 27025386); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 9099841, 9600589, 11325342, 27025386, 37284795, 35938991, 31069529, 9328258, 35383424) -

Dec 29, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and segregates with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.105C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced channel conductance (PMID: 11325342). -

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

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Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 15 of the GJB1 protein (p.Arg15Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT (PMID: 9099841, 9328258, 9600589, 10521546, 11835375, 21149811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21084). 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 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 11325342, 22771394). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D;.;D;.;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.52
MutPred		0.84		Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.97

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: rs116840815; hg19: chrX-70443600;