rs1555937135

chrX-71224010-AGAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM4_Supporting PP5_Moderate

The NM_000166.6(GJB1):c.304_306del(p.Glu102del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2
• Conservation: PhyloP100: 7.34

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000166.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000166.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-71224010-AGAG-A is Pathogenic according to our data. Variant chrX-71224010-AGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 477594.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71224010-AGAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.304_306del	p.Glu102del	inframe_deletion	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.304_306del	p.Glu102del	inframe_deletion	2/2
GJB1	XM_011530907.3	c.304_306del	p.Glu102del	inframe_deletion	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.304_306del	p.Glu102del	inframe_deletion	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2003	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2018

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu102 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 8004109, 14627639, 17353473), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this variant disrupts the formation of gap junction plaques (PMID: 28071741). This variant has been observed to segregate in several families affected with X-linked Charcot-Marie-Tooth disease (CMTX) (PMID: 12707076, Invitae). ClinVar contains an entry for this variant (Variation ID: 477594). This variant is not present in population databases (ExAC no frequency). This variant, c.304_306delGAG, results in the deletion of 1 amino acid of the GJB1 protein (p.Glu102del), but otherwise preserves the integrity of the reading frame. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1555937135; hg19: chrX-70443860;