rs879254099

Positions:

• chrX-71224350-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.643C>T​(p.Arg215Trp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 2.09

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 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-71224351-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219704.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-71224350-C-T is Pathogenic according to our data. Variant chrX-71224350-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224350-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.643C>T	p.Arg215Trp	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.643C>T	p.Arg215Trp	missense_variant	2/2
GJB1	XM_011530907.3	c.643C>T	p.Arg215Trp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.643C>T	p.Arg215Trp	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (Omori et al., 1996; Castro et al., 1999).; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10234007, 11835375, 8816997, 8162049, 11571214, 32376792) -

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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2023	Variant summary: GJB1 c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179956 control chromosomes. c.643C>T has been reported in the literature in multiple familial individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example, Fairweather_1994, Kovale_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal GJB1 levels, diminished gap junctional intercellular communication, and interfering WT allele of GJB1 through a dominant-negative mechanism in Hela cells (Omori_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8162049, 34326750, 8816997). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 25, 2023	Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP3 -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 215 of the GJB1 protein (p.Arg215Trp). 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 (CMT1X) (PMID: 8162049, 8698335, 9187667, 11437164, 11571214, 11835375, 16912585, 22464564, 25947624, 27098783). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246098). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;D;D;D
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.97	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D;.;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.57
MutPred		0.82		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
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: rs879254099; hg19: chrX-70444200;