X-71223249-C-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000166.6(GJB1):c.-103C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000111 in 89,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.000011 ( 0 hom. 0 hem. )
Consequence
GJB1
NM_000166.6 5_prime_UTR
NM_000166.6 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.40
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-71223249-C-T is Pathogenic according to our data. Variant chrX-71223249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223249-C-T is described in Lovd as [Pathogenic]. Variant chrX-71223249-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.39). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB1 | NM_000166.6 | c.-103C>T | 5_prime_UTR_variant | Exon 1 of 2 | ENST00000361726.7 | NP_000157.1 | ||
| GJB1 | NM_001097642.3 | c.-16-443C>T | intron_variant | Intron 1 of 1 | NP_001091111.1 | |||
| GJB1 | XM_011530907.3 | c.-16-443C>T | intron_variant | Intron 1 of 1 | XP_011529209.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome AF: 0.0000111 AC: 1AN: 89798Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 22780
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GnomAD4 genome
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Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:7
| Likely pathogenic, criteria provided, single submitter | research | Pangenia Genomics, Pangenia Inc. | Oct 14, 2022 | The GJB1, c.-103C>T variant was detected in multiple affected family members with a clinical diagnosis of CMT. The variant has also been reported in multiple families of various ethnicities to co-segregate with CMT (PMID: 8757034, 10671058, 19335535, 21918739, 28283593). This variant was reported to affect an IRES (internal ribosomal entry site) and subsequently the translation of GJB1 by luciferase reporter assays in transgenic mice and transfected cells (previously reported as c.-459C>T and c.-458C>T in the literature, PMID: 10931843, 23827825), although a recent study did not recapitulate the results (PMID: 34089394). This variant is found only once in African population in gnomAD genomes, and not found in East Asian population in gnomAD genomes. Furthermore, this variant has been detected in multiple unrelated patients with CMT from various countries (PMID: 18379723, 23827825, 26392352, 28768847, 31211173, 31920494, 33136338, 31827005), and not detected in controls in some studies (PMID: 8757034, 19335535). - |
| Pathogenic, no assertion criteria provided | provider interpretation | Codex Genetics Limited | Feb 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2024 | Variant summary: GJB1 c.-103C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 21640 control chromosomes (gnomAD). c.-103C>T has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (Record_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 37284795). ClinVar contains an entry for this variant (Variation ID: 217166). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jan 05, 2024 | This sequence change in GJB1 is located in the 5' untranslated promotor (P2) region (PMID: 20301548). Multiple functional studies using rat models and luciferase functional studies, assessing protein translation at the internal ribsome entry site (IRES) showed conflicting results suggesting the mechanism of disease is still unknown and requires further investigation (PMID: 34089394, 10931843, 23827825). This variant is present in a single individual from the East Asian population in the population database gnomAD v4.0 (1/4994 alleles). This variant has also been reported as c.-459C>T in the literature. This variant has been reported in multiple unrelated individuals with Charcot-Marie-Tooth (CMT) neuropathy and segregates with disease in at least two families (PMID: 19335535, 37284795, 23827825, 26392352, 28283593, 31827005, 31211173, 18379723, 31920494, ClinVar ID: 217166). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Strong, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Aug 01, 2023 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 06, 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. In some published literature, this variant is referred to as c.-458C>T or c.-459C>T. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly affects translation by disrupting an Internal Ribosome Entry Site (IRES) (PMID: 10931843, 23827825, 34089394). - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | GJB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2023 | Published functional studies indicate impaired protein expression (PMID: 10931843, 23827825); No data available from ethnically-matched control populations to assess the frequency of this variant; Also known as c.-459 C>T; This variant is associated with the following publications: (PMID: 31211173, 28283593, 23827825, 8757034, 31827005, 33136338, 34089394, 19335535, 26392352, 10931843) - |
Charcot-Marie-Tooth disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2025 | This variant occurs in a non-coding region of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8757034, 19335535, 23827825, 26392352, 28283593, 28768847). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-458C>T and c.-459C>T. ClinVar contains an entry for this variant (Variation ID: 217166). Studies have shown that this variant alters GJB1 gene expression (PMID: 10931843, 23827825). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at