rs116840815

chrX-71223750-C-T

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.43C>T(p.Arg15Trp) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:1
• Conservation: PhyloP100: 3.18

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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-71223751-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1709368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant X-71223750-C-T is Pathogenic according to our data. Variant chrX-71223750-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223750-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.43C>T	p.Arg15Trp	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.43C>T	p.Arg15Trp	missense_variant	2/2
GJB1	XM_011530907.3	c.43C>T	p.Arg15Trp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.43C>T	p.Arg15Trp	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2022	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and segregates with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.105C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced channel conductance (PMID: 11325342). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2018	The R15W mutation has been previously reported in association with Charcot-Marie-Tooth neuropathy (Wicklein et al., 1997), and functional studies show that the R15W mutation significantly alters the channel function (Abrams et al., 2001). Additionally, a different amino acid substitution at the same position (R15Q) and other missense mutations in nearby residues (V13L/M, N14S, H16L/P/Q) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. R15W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 15 of the GJB1 protein (p.Arg15Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT (PMID: 9099841, 9328258, 9600589, 10521546, 11835375, 21149811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21084). 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. Experimental studies have shown that this missense change affects GJB1 function (PMID: 11325342, 22771394). For these reasons, this variant has been classified as Pathogenic. -

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.5	D;.;D;.;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.52
MutPred		0.84		Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.97

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: rs116840815; hg19: chrX-70443600;