rs1555937233

chrX-71224255-G-AchrX-71224255-G-C

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.548G>A(p.Arg183His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,732 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 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-71224254-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-71224255-G-A is Pathogenic according to our data. Variant chrX-71224255-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224255-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.548G>A	p.Arg183His	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.548G>A	p.Arg183His	missense_variant	2/2
GJB1	XM_011530907.3	c.548G>A	p.Arg183His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.548G>A	p.Arg183His	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093732 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1 AN XY: 360942

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 10, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with X-linked Charcot-Marie-Tooth neuropathy, type 1 (CMTX1). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes aberrant cellular localization of this gap junction protein (PMID: 12111842). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Computational tools predict that this variant is damaging. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The p.R183H pathogenic mutation (also known as c.548G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 548. The arginine at codon 183 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in several different families of various origin (Bort S et al. Hum Genet, 1997 Jun;99:746-54; Mersiyanova IV et al. Hum Mutat, 2000;15:340-7; Hattori N et al. Brain, 2003 Jan;126:134-51; Chen CX et al. Ann Clin Transl Neurol, 2020 12;7:2381-2392; Kochaski A et al. J Appl Genet, 2004;45:95-100; Niu J et al. Front Neurol, 2019 Jan;10:1406; Chen B et al. Clin Neurol Neurosurg, 2019 Sep;184:105430; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Zhang RX et al. Beijing Da Xue Xue Bao Yi Xue Ban, 2005 Feb;37:68-71; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Micheau P et al. Ann Chir Plast, 1975;20:311-8). Experimental studies show this alteration led to abnormal protein function (Kleopa KA et al. J Neurosci Res, 2002 Jun;68:522-34). (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the GJB1 protein (p.Arg183His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type X (PMID: 9187667, 14960772, 15719046, 27027447, 27844031, 28469099). ClinVar contains an entry for this variant (Variation ID: 447435). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12111842, 27844031). This variant disrupts the p.Arg183 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9187667, 11271367, 12111842). 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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;D
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	D;.;D;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.024	D;.;D;.;D
Sift4G	Uncertain	0.014	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.94
MutPred		0.91		Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
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: rs1555937233; hg19: chrX-70444105; COSMIC: COSV100661308; COSMIC: COSV100661308;