rs1555937156

Variant names:

• chrX-71224067-GAAGAGGCAC-G
• rs1555937156
• NM_000166.6:c.364_372delAGGCACAAG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_000166.6(GJB1):​c.364_372delAGGCACAAG​(p.Arg122_Lys124del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R122R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 16 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000166.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.364_372delAGGCACAAG	p.Arg122_Lys124del	conservative_inframe_deletion	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.364_372delAGGCACAAG	p.Arg122_Lys124del	conservative_inframe_deletion	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.364_372delAGGCACAAG	p.Arg122_Lys124del	conservative_inframe_deletion	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.364_372delAGGCACAAG	p.Arg122_Lys124del	conservative_inframe_deletion	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.364_372del, results in the deletion of 3 amino acid(s) of the GJB1 protein (p.Arg122_Lys124del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 447431). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555937156; hg19: chrX-70443917;