Genetic Variant GJB1:c.-103C>T (chrX-71223249-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

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

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]

GJB1 links:

Genome browser will be placed here

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	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.-103C>T	5_prime_UTR_variant	Exon 1 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.-16-443C>T	intron_variant	Intron 1 of 1		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.-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
GJB1	ENST00000361726 link	c.-103C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000111

AC:

AN:

89798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

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

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

- -

Feb 28, 2019

Codex Genetics Limited

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

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 -

Jun 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). -

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. -

not provided

Pathogenic:3

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) -

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 -

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over