rs1555937270
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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E208G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.622G>A | p.Glu208Lys | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
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 genome ? Cov.: 21
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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 | - - |
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) - |
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 | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at