rs1060501002

Variant names:

• chrX-71223772-G-A
• rs1060501002
• NM_000166.6:c.65G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71223772-G-A
• chrX-71223772-G-C

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.65G>A​(p.Arg22Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,374 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2
• Conservation: PhyloP100: 4.63

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, 0.992
• PP5: Variant X-71223772-G-A is Pathogenic according to our data. Variant chrX-71223772-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223772-G-A is described in Lovd as [Pathogenic]. Variant chrX-71223772-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.65G>A	p.Arg22Gln	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.65G>A	p.Arg22Gln	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	XM_011530907.3	c.65G>A	p.Arg22Gln	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.65G>A	p.Arg22Gln	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097374 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362746

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.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:5 Uncertain:1

Apr 25, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as heterozygous or hemizygous change in patients with Charcot-Marie-Tooth disease (PMID: 7580242, 12542510). The variant has been reported as pathogenic by two clinical laboratories in the ClinVar database (SCV000544775, SCV000613500). In vitro studies on the functional impact of the p.Arg22Gln variant are conflicting (PMID: 11393532, 15006706). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.65G>A (p.Arg22Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.65G>A (p.Arg22Gln) variant is classified as likely pathogenic. -

Feb 10, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in GJB1 is predicted to replace arginine with glutamine at codon 22, p.(Arg22Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a transmembrane region. There is a small physicochemical difference between arginine and glutamine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least 11 probands with Charcot-Marie-Tooth neuropathy type 1/1X (CMT1/CMT1X; PMID: 7580242, 9272161, 26454100, 29998508, 33314704). The variant has been reported to segregate with neuropathy in at least four families, including affected females with less severe disease (PMID: 7580242, 9272161, 18358413). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with CMT1 (PMID: 9272161). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS2_Moderate, PS4_Moderate, PM2_Supporting, PP3. -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Apr 03, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM1, PM2, PM5, PM6, PS4 -

May 05, 2023

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. This variant associates with disease in multiple families, and has been found de novo in at least one case (PMID: 9272161). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -

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

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Nov 15, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R22Q variant (also known as c.65G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 65. The arginine at codon 22 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported to cosegregate with disease in multiple unrelated patients and families with CMTX (Boerkoel CF et al. Ann. Neurol., 2002 Feb;51:190-201; Senderek J et al. J. Neurol. Sci., 1999 Aug;167:90-101; Silander K et al. Hum. Genet., 1997 Sep;100:391-7; Takashima H et al. Acta Neurol. Scand., 2003 Jan;107:31-7). De novo occurrence has also been reported in an affected patient (Silander K et al. Hum. Genet., 1997 Sep;100:391-7). The functional mechanism of this alteration remains to be elucidated and experimental studies performed in different cell lines have shown conflicting results as protein localization and channel formation were aberrant in PC12 cells (Matsuyama W et al. J. Hum. Genet., 2001;46:307-13) but preserved in N2A cells (Wang HL et al. Neurobiol. Dis., 2004 Mar;15:361-70). In addition to the clinical data presented in the literature, this alteration is predicted to be deleterious by in silico analysis, and is not reported in population-based 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

Jan 08, 2025

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 glutamine, which is neutral and polar, at codon 22 of the GJB1 protein (p.Arg22Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (CMT) (PMID: 7580242, 8737658, 9272161, 9600589, 9633821, 10521546, 11835375, 12542510, 17353473, 26454100). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406228). 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) has been performed 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 11393532, 15006706). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M;M;.;.;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D;.;D;.;D;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.024	D;.;D;.;D;.;D
Sift4G	Uncertain	0.026	D;.;D;.;D;.;D
Polyphen		0.99	D;D;D;D;.;.;D
Vest4		0.84
MutPred		0.98		Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);Loss of MoRF binding (P = 0.0096);
MVP		1.0
MPC		2.0
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.89
gMVP		0.99

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: rs1060501002; hg19: chrX-70443622;