rs1555937270
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.622G>A(p.Glu208Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 21)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )
Consequence
GJB1
NM_000166.6 missense
NM_000166.6 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 9.99
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant X-71224329-G-A is Pathogenic according to our data. Variant chrX-71224329-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224329-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | NP_001091111.1 | ||
GJB1 | XM_011530907.3 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | XP_011529209.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | 1 | NM_000166.6 | ENSP00000354900 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD3 genomes
Cov.:
21
GnomAD4 exome AF: 9.12e-7 AC: 1AN: 1096756Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1AN XY: 362496
GnomAD4 exome
AF:
AC:
1
AN:
1096756
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
362496
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 21
GnomAD4 genome
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2023 | Published functional studies demonstrate the variant results in impaired intracelluar trafficking of the protein to the plasma membrane (Deschenes et al., 1997; Wang et al., 2004); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31372974, 32047472, 9592087, 9364054, 10848620, 17646144, 26454100, 15006706, 29629536, 27549087, 8162049, 14960772) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2020 | The p.E208K pathogenic mutation (also known as c.622G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 622. The glutamic acid at codon 208 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in individuals with Charcot-Marie-Tooth neuropathy and has been reported to segregate with disease in families (Fairweather N et al. Hum Mol Genet, 1994 Jan;3:29-34; Feng SY et al. J Clin Neurol, 2018 Apr;14:261-263). Additionally, studies have shown that this alteration affects the function of the GJB1 protein (Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Ressot C et al. J Neurosci, 1998 Jun;18:4063-75; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46; Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 208 of the GJB1 protein (p.Glu208Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8162049, 10737979, 14960772, 17646144, 25429913, 28448691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447439). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 9592087, 10848620, 15006706). This variant disrupts the p.Glu208 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14960772). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D;D
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;.;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;D
Sift4G
Pathogenic
D;.;D;.;D
Polyphen
D;D;D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);Gain of MoRF binding (P = 0.0042);
MVP
MPC
2.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at