rs879253909

chrX-71224248-G-AchrX-71224248-G-CchrX-71224248-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000166.6(GJB1):c.541G>A(p.Val181Met) 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. V181E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 2.94

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 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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-71224249-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant X-71224248-G-A is Pathogenic according to our data. Variant chrX-71224248-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 245705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224248-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.541G>A	p.Val181Met	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.541G>A	p.Val181Met	missense_variant	2/2
GJB1	XM_011530907.3	c.541G>A	p.Val181Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.541G>A	p.Val181Met	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

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9361298, 17100997, 31372974, 19259128, 21692908, 25947624, 28071741, 32903794, 33136338) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 181 of the GJB1 protein (p.Val181Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 9361298, 17100997, 19259128, 21692908, 25947624). ClinVar contains an entry for this variant (Variation ID: 245705). 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%. This variant disrupts the p.Val181 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 14627639, 18380028), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 24, 2022

The GJB1 c.541G>A variant is classified as a LIKLEY PATHOGENIC VARIANT (PM2, PP2, PP3, PS4_S, PM1_S, PM5_S) This variant is a single nucleotide change in exon 2/2 of the GJB1 gene, which is predicted to change the amino acid valine at position 181 in the protein to methionine. The variant is located in a mutational hot spot (PM1_S). Missense variant in the GJB1 gene are a common mechanism of disease, and has a low rate of benign missense variation (PP2). This variant is at an amino acid residue where several different missense changes determined to be pathogenic have been reported previously (PM5_S). The variant has been reported in dbSNP (rs879253909) but is absent from population databases (PM2). The variant has been repored in ClinVar (VariationID: #245705) and HGMD (Accession: CM973178) as pathogenic/ disease causing variant (PS4_S). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;D
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N;.;N;.;N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Benign	0.10	T;.;T;.;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.39
MutPred		0.64		Loss of catalytic residue at V181 (P = 0.0888);Loss of catalytic residue at V181 (P = 0.0888);Loss of catalytic residue at V181 (P = 0.0888);Loss of catalytic residue at V181 (P = 0.0888);Loss of catalytic residue at V181 (P = 0.0888);
MVP		1.0
MPC		1.8
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
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: rs879253909; hg19: chrX-70444098; COSMIC: COSV62139949; COSMIC: COSV62139949;