rs879254047

Positions:

• chrX-71223335-G-A

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.-17G>A variant causes a splice region, 5 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.9193
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.58

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-71223335-G-A is Pathogenic according to our data. Variant chrX-71223335-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223335-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.-17G>A		splice_region_variant, 5_prime_UTR_variant	1/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.-16-357G>A		intron_variant			NP_001091111.1
GJB1	XM_011530907.3	c.-16-357G>A		intron_variant			XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.-17G>A		splice_region_variant, 5_prime_UTR_variant	1/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 11, 2020	The GJB1 c.-17G>A variant occurs in the last base of the 5' untranslated region. This variant has been reported in at least four studies, in which it is found in a total of 26 individuals from eight unrelated families with Charcot-Marie-Tooth neuropathy X type 1 disorder (CMT1X) (Murphy et al. 2011; Arthur-Farraj et al. 2012; Antoniadi et al. 2015; Tomaselli et al. 2017). Affected individuals included both heterozygous females and hemizygous males, and this variant was shown to segregate with disease in five families (Murphy et al. 2011; Tomaselli et al. 2017). The c.-17G>A variant is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the c.-17G>A variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	Variant summary: GJB1 c.-17G>A (also known as -373G>A) is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 21639 control chromosomes. c.-17G>A has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example: Murphy_2011). 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: 21504505). ClinVar contains an entry for this variant (Variation ID: 246014). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2021	No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 23011429, 22464564, 28768847, 26392352, 31827005, 21504505, 28283593) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2020	Not found in the gnomAD genomes dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Splicing predictions are inconclusive. Nucleotide conservation is uninformative. Strong co-segregation with disease, and data includes affected and unaffected individuals from multiple families. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

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. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. 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: 21504505, 22464564, 26392352, 28283593, 28768847; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-373G>A. ClinVar contains an entry for this variant (Variation ID: 246014). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.0		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: rs879254047; hg19: chrX-70443185;