rs768834663

chrX-71223790-T-AchrX-71223790-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000166.6(GJB1):c.83T>A(p.Ile28Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I28T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.99

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 11 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-71223790-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246094.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-71223790-T-A is Pathogenic according to our data. Variant chrX-71223790-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215983.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}. Variant chrX-71223790-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.83T>A	p.Ile28Asn	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.83T>A	p.Ile28Asn	missense_variant	2/2
GJB1	XM_011530907.3	c.83T>A	p.Ile28Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.83T>A	p.Ile28Asn	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183311 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

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

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 28 of the GJB1 protein (p.Ile28Asn). This variant is present in population databases (rs768834663, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1X (PMID: 9361298; Invitae). ClinVar contains an entry for this variant (Variation ID: 215983). 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 missense change is located in a region of the GJB1 protein in which a significant number of missense variants have been reported (PMID: 21309765). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 15, 2019

The GJB1 p.Ile28Asn variant (rs768834663) was reported in a cohort of patients with CMT from Athena diagnostics (Bone, 1997). Among the 130 variants reported in this cohort, several affecting the same codon (c.83T>C; p.Ile28T) or nearby residues (p.Ser26Leu, p.Val27Ala and p.Ile30Asn) were observed in affected patients. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0005 percent (identified on 1 out of 183,311 chromosomes), and reported to ClinVar as a pathogenic variant (Variation ID: 215983). The isoleucine at position 28 is highly conserved across the vertebrates and located in a transmembrane domain. Computational analyses of the p.Ile28Asn variant on protein structure and function indicates a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on these observations, the p.Ile28Asn variant is likely to be pathogenic. References: Bone et al. Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 1997;4(3-4):221-30. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

The p.I28N variant (also known as c.83T>A), located in coding exon 1 of the GJB1 gene, results from a T to A substitution at nucleotide position 83. The isoleucine at codon 28 is replaced by asparagine, an amino acid with dissimilar properties. This alteration was detected in a cohort of patients with Charcot–Marie–Tooth disease (Bone LJ et al. Neurobiol. Dis., 1997;4:221-30). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183,311) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.001% (1/81,818) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L;L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D;.;D;.;D;.;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;D;.;D
Polyphen		0.99	D;D;D;D;.;.;D
Vest4		0.93
MutPred		0.94		Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);
MVP		0.98
MPC		2.3
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.92
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: rs768834663; hg19: chrX-70443640;