X-71223249-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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]

ACMG classification

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/exons	MANE	UniProt
GJB1	NM_000166.6	c.-103C>T		5_prime_UTR_variant	1/2	ENST00000361726.7
GJB1	NM_001097642.3	c.-16-443C>T		intron_variant
GJB1	XM_011530907.3	c.-16-443C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.-103C>T		5_prime_UTR_variant	1/2	1	NM_000166.6	P1

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

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:6

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, 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. c.-103C>T has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	provider interpretation	Codex Genetics Limited	Feb 28, 2019	- -
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	Revvity Omics, Revvity	Jun 06, 2023	- -

not provided Pathogenic:3

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) -
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 -

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

Invitae

Dec 19, 2023

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

Other links and lift over

dbSNP: rs863224971; hg19: chrX-70443099;