X-71223249-C-T

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

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.40
Variant links:
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
GJB1NM_000166.6 linkc.-103C>T 5_prime_UTR_variant Exon 1 of 2 ENST00000361726.7 NP_000157.1 P08034A0A654ICJ7
GJB1NM_001097642.3 linkc.-16-443C>T intron_variant Intron 1 of 1 NP_001091111.1 P08034A0A654ICJ7
GJB1XM_011530907.3 linkc.-16-443C>T intron_variant Intron 1 of 1 XP_011529209.1 P08034A0A654ICJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB1ENST00000361726 linkc.-103C>T 5_prime_UTR_variant Exon 1 of 2 1 NM_000166.6 ENSP00000354900.6 P08034

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.0000111
AC:
1
AN:
89798
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
22780
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000200
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
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
Oct 14, 2022
Pangenia Genomics, Pangenia Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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). -

Feb 28, 2019
Codex Genetics Limited
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

- -

Mar 15, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 06, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 05, 2024
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

Mar 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2023
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Oct 06, 2021
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Mar 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

GJB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -

Oct 30, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Jan 21, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.39
CADD
Benign
19
DANN
Benign
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224971; hg19: chrX-70443099; API