X-71223930-C-T

Position:

• chrX-71223930-C-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.223C>T​(p.Arg75Trp) variant causes a missense change. 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: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 4.92

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, 0.994
• PP5: Variant X-71223930-C-T is Pathogenic according to our data. Variant chrX-71223930-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223930-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.223C>T	p.Arg75Trp	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.223C>T	p.Arg75Trp	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.223C>T	p.Arg75Trp	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.223C>T	p.Arg75Trp	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1092506 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 358516

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2023	Published functional studies demonstrate a damaging effect on the gene product (PMID: 12460545, 23209285); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (R75Q) and (R75P) have been reported in the Human Gene Mutation Database and in published literature (PMID: 8829637, 9272161, 23209285, 12460545, 32489946, 32399692; HGMD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19369543, 9361298, 14663027, 12460545, 12402337, 17100997, 23209285, 30373780, 29095325, 32941234, 32399692, 9272161, 10732813, 8829637, 32489946) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 23, 2023	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed defective protein activity and transgenic mice with a demyelinating neuropathy (PMID: 12460545, 19369543, 23209285, 28334782). -

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

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 11, 2019	The GJB1 c.223C>T; p.Arg75Trp variant (rs116840819) is reported frequently in the literature in individuals affected with X-linked Charcot-Marie-Tooth neuropathy (select references: Silander 1997, Zhang 2005, Parissis 2017, and Bacquet 2018). Functional analyses of the variant protein in cell culture and transgenic mice show that the p.Arg75Trp variant causes defects in GJB1 protein function consistent with known CMT disease mechanisms (Sargiannidou 2009, Abrams 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 26, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The p.R75W variant (also known as c.223C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 223. The arginine at codon 75 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in the hemizygous state in multiple unrelated males with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), as well as in heterozygous carrier females with mild symptoms (Vogt B et al. J Neurol, 2020 Sep;267:2648-2654; Silander K et al. Hum Genet, 1997 Sep;100:391-7; Zhang RX et al. Beijing Da Xue Xue Bao Yi Xue Ban, 2005 Feb;37:68-71; Parissis D et al. Neurologist, 2017 Nov;22:234-236). Functional studies indicate this alteration impairs gap junction formation and transgenic mice expressing this alteration recapitulate the phenotype (Kagiava A et al. Hum Mol Genet, 2018 04;27:1460-1473; Kyriakoudi S et al. Hum Mol Genet, 2017 05;26:1622-1633; Abrams CK et al. J Biol Chem, 2013 Feb;288:3609-19; Sargiannidou I et al. J Neurosci, 2009 Apr;29:4736-49). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 75 of the GJB1 protein (p.Arg75Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 9272161, 10732813, 12402337, 14663027, 15719046, 17100997). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21082). 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%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12460545, 19369543, 23209285). For these reasons, this variant has been classified as Pathogenic. -

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	0.87
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.;.;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.0	D;.;D;.;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.92
MutPred		0.99		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116840819; hg19: chrX-70443780;