X-71223858-T-C

Variant names:

• chrX-71223858-T-C
• rs876661269
• NM_000166.6:c.151T>C

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.151T>C​(p.Phe51Leu) 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F51S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.02
• Publications: 7 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 21 ACMG points.

• PS1: Transcript NM_000166.6 (GJB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.983
• PP5: Variant X-71223858-T-C is Pathogenic according to our data. Variant chrX-71223858-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 234871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.151T>C	p.Phe51Leu	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.151T>C	p.Phe51Leu	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.151T>C	p.Phe51Leu	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.151T>C	p.Phe51Leu	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate loss of plaque formation compared to wildtype, and impaired docking with hemichannels on neighboring cells (PMID: 28071741); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31372974, 26454100, 28768847, 28071741) -

Oct 16, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 28071741) -

Inborn genetic diseases Pathogenic:1

Jun 10, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F51L variant (also known as c.151T>C), located in coding exon 1 of the GJB1 gene, results from a T to C substitution at nucleotide position 151. The phenylalanine at codon 51 is replaced by leucine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with Charcot-Marie-Tooth disease (Wang R et al. Clin Chim Acta, 2015 Dec;451:263-70; Abrams CK et al. Sci Rep, 2017 01;7:40166; Panosyan FB et al. Neurology, 2017 Aug;89:927-935; Chen CX et al. Clin Genet, 2019 11;96:439-448; Ambry internal data). In one experimental study, this alteration appeared to impair gap junction formation (Abrams CK et al. Sci Rep, 2017 01;7:40166). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 51 of the GJB1 protein (p.Phe51Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 26454100, 28071741; internal datadatabase). ClinVar contains an entry for this variant (Variation ID: 234871). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 28071741). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;.;.;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D;.;D;.;D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.015	D;.;D;.;D;.;D
Sift4G	Uncertain	0.036	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.97
MutPred		0.89		Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);Gain of glycosylation at S50 (P = 0.1358);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.81
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs876661269; hg19: chrX-70443708;