X-71224197-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000166.6(GJB1):c.490C>T(p.Arg164Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,203,185 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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, 0.901

PP5

Variant X-71224197-C-T is Pathogenic according to our data. Variant chrX-71224197-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224197-C-T is described in Lovd as [Pathogenic]. Variant chrX-71224197-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 2 of 2		XP_011529209.1	P08034A0A654ICJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.00000909

AC:

AN:

109963

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32205

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000582

AC:

AN:

171957

Hom.:

AF XY:

0.00

AC XY:

AN XY:

58379

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1093222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359346

show subpopulations

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:

0.0000218

GnomAD4 genome

AF:

0.00000909

AC:

AN:

109963

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32205

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 27, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15006706) The variant is located in a region that is considered important for protein function and/or structure. -

Jul 29, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R164W pathogenic variant has been published numerous times in association with CMT (Ionasescu et al., 1995; Ionasescu et al., 1996; Oterino et al., 1996; Young et al., 2001). Functional studies using dual whole-cell voltage-clamp recordings show that R164W impaired the formation and function of junctional channels (Wang et al., 2004). Additionally, different amino acid substitutions at this same position (R164G/Q) and in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional significance of this region of the protein. R164W was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. R164W is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, R164W is interpreted to be a pathogenic variant. -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Nov 18, 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 164 of the GJB1 protein (p.Arg164Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 7580242, 8733054, 11437164, 28469099). It has also been observed to segregate with disease in related individuals. This variant is also known as c.552C>T. ClinVar contains an entry for this variant (Variation ID: 217170). 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 have shown that this missense change affects GJB1 function (PMID: 11571214, 15006706). This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9187667, 25025039, 27844031). 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

Mar 11, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;D;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

.;.;.;.;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.1

M;M;M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.8

D;.;D;.;D

REVEL

Pathogenic

0.81

Sift

Benign

0.15

T;.;T;.;T

Sift4G

Benign

0.19

T;.;T;.;T

Polyphen

0.99

D;D;D;D;D

Vest4

0.94

MVP

1.0

MPC

1.9

ClinPred

0.92

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over