X-71223771-C-T

Variant names:

• chrX-71223771-C-T
• rs1555937020
• NM_000166.6:c.64C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000166.6(GJB1):​c.64C>T​(p.Arg22*) variant causes a stop gained 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: 22)
• Consequence: GJB1 NM_000166.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 U:2
• Conservation: PhyloP100: 3.31
• Publications: 1 publications found

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]

GJB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 245 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71223771-C-T is Pathogenic according to our data. Variant chrX-71223771-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 447441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.64C>T	p.Arg22*	stop_gained	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB1: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4 -

Mar 22, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 27228968, 8698335, 21692908, 18379723, 9401007, 21291455, 28768847, 24123415, 8004109) -

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

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2024

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in the N-terminus connexin domain together with other pathogenic variants. PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PP1 met: variant segregates with 3 informative meioses in 1 family (PMID: 8698335). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

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

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Nov 01, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu, 1994; Rouger, 1997; Mandich, 2008; Dubourg, 2001). Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg22*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X (CMTX) (PMID: 8004109, 9401007, 11571214, 21692908). 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: 447441). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		3.3
Vest4		0.83
GERP RS		4.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555937020; hg19: chrX-70443621;