X-71223784-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.77C>T(p.Ser26Leu) variant causes a missense change involving the alteration of a 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. S26W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.88

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-71223784-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 477604.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-71223784-C-T is Pathogenic according to our data. Variant chrX-71223784-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 155726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223784-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.77C>T	p.Ser26Leu	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.77C>T	p.Ser26Leu	missense_variant	2/2
GJB1	XM_011530907.3	c.77C>T	p.Ser26Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.77C>T	p.Ser26Leu	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 29, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/204891 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in affected and unaffected individuals, but from a single family. One de novo case without parental identity confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	The S26L missense variant in the GJB1 gene has been reported previously in association with CMTX1 (Oh et al., 1997; Nelis et al., 1997; Sun et al., 2016). Functional analysis shows that S26L alters the structure and permeability of the membrane (Oh et al., 1997). The S26L variant is not observed in large population cohorts (Lek et al., 2016). The S26L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with CMTX1 (Stenson et al., 2014). Therefore, S26L is interpreted to be a pathogenic variant. -

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

Pathogenic, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 12, 2021	The GJB1 c.77C>T; p.Ser26Leu variant (rs587777876) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (selected references: Yoshimura 1996, Hsu 2019, and Niu 2020). In vitro functional analyses demonstrate that the p.Ser26Leu alters the channels junctional permeability by reducing the pore size (Tsai 2016). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 26 of the GJB1 protein (p.Ser26Leu). 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 1X (PMID: 8990008, 9354338, 11271367, 21291455, 25429913, 25802885, 27862672). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155726). 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: 9354338, 16442804, 27844031). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D;.;D;.;D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;T;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.94
MutPred		0.94		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.88
gMVP		0.99

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: rs587777876; hg19: chrX-70443634;