rs876661252

chrX-71224249-T-AchrX-71224249-T-C

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.542T>A(p.Val181Glu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.02

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 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant X-71224249-T-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.542T>A	p.Val181Glu	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.542T>A	p.Val181Glu	missense_variant	2/2
GJB1	XM_011530907.3	c.542T>A	p.Val181Glu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.542T>A	p.Val181Glu	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val181 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9361298, 17100997, 19259128, 21692908, 25947624). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 234844). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 181 of the GJB1 protein (p.Val181Glu). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 2021

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;D;D;D
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.8	D;.;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.79
MutPred		0.80		Gain of disorder (P = 0.0056);Gain of disorder (P = 0.0056);Gain of disorder (P = 0.0056);Gain of disorder (P = 0.0056);Gain of disorder (P = 0.0056);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0

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: rs876661252; hg19: chrX-70444099;