X-71224209-T-G

Variant names:

• chrX-71224209-T-G
• rs1057518780
• NM_000166.6:c.502T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000166.6(GJB1):​c.502T>G​(p.Cys168Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C168Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.02
• 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71224209-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 807752.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-71224209-T-G is Pathogenic according to our data. Variant chrX-71224209-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373934.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.502T>G	p.Cys168Gly	missense	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.502T>G	p.Cys168Gly	missense	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.502T>G	p.Cys168Gly	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.502T>G	p.Cys168Gly	missense	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.502T>G	p.Cys168Gly	missense	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.502T>G	p.Cys168Gly	missense	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hand muscle atrophy;C0728829:Pes cavus;C1389118:Peroneal muscle atrophy;C1836450:Distal lower limb muscle weakness Pathogenic:1

Aug 10, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sensory neuropathy;C0427065:Distal muscle weakness;C0728829:Pes cavus;C1136179:Hammertoe;C1857640:Decreased nerve conduction velocity Pathogenic:1

Nov 27, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP3,PP5.

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 168 of the GJB1 protein (p.Cys168Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373934). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB1 protein function with a positive predictive value of 80%. This variant disrupts the p.Cys168 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 12325071, 15241803), which suggests that this may be a clinically significant amino acid residue. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.71		Loss of stability (P = 0.0058)
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1057518780; hg19: chrX-70444059;