rs779696968

chrX-71224012-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):c.305A>G(p.Glu102Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102Q) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• 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 Pathogenic. Variant got 16 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant X-71224012-A-G is Pathogenic according to our data. Variant chrX-71224012-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 216038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224012-A-G is described in Lovd as [Pathogenic]. Variant chrX-71224012-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.305A>G	p.Glu102Gly	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.305A>G	p.Glu102Gly	missense_variant	2/2
GJB1	XM_011530907.3	c.305A>G	p.Glu102Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.305A>G	p.Glu102Gly	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111228 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33470

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000118 AC: 2 AN: 169210 Hom.: 0 AF XY: 0.0000181 AC XY: 1 AN XY: 55218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111228 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2019	PS3, PS4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	Published functional studies demonstrate a damaging effect (homotypic channels differ from wild type in sensitivity and time course; impairs modulatory function of Schwann cells on axons, resulting in profound cytoskeletal alterations leading to distal axonal degeneration) (Ressot et al., 1998; Sahenk et al., 1998); Missense variants in this gene are often considered pathogenic (HGMD); 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: 9354338, 22771394, 25614874, 8004109, 9592087, 8737658, 17353473, 14627639, 9469571, 31827005, 11835375, 10873293) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant has frequently been reported to result in a milder phenotype in patients when compared to complete loss-of-function variants (PMID: 8737658, 14627639, 27228968). In some published literature, this variant is referred to as 367A>G. Assessment of experimental evidence suggests this variant results in abnormal protein function. In functional studies, this variant formed channels, but these displayed abnormal voltage gating and dysfunction during acidification (consistent with the milder phenotype reported), as well as lower myelinated fiber density (PMID: 9592087, 14627639). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The p.E102G variant (also known as c.305A>G), located in coding exon 1 of the GJB1 gene, results from an A to G substitution at nucleotide position 305. The glutamic acid at codon 102 is replaced by glycine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals affected with X-linked Charcot-Marie-Tooth disease (CMT) and was confirmed de novo in one individual as well as shown to segregate with the disease in another family (Ionasescu V et al. Hum. Mol. Genet., 1994 Feb;3:355-8; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84; Boerkoel CF et al. Ann. Neurol., 2002 Feb;51:190-201; Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58; Siskind CE et al. J Peripher Nerv Syst, 2011 Jun;16:102-7; Record CJ et al. Brain, 2023 Oct;146:4336-4349). Experimental studies have shown that nerve xenografts from the patients with E102G showed altered Schwann cell membrane composition/organization, leading to axonal abnormalities (Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84). Moreover, studies using Xenopus oocytes showed that this variant increased sensitivity of channels to intracellular acidification, affecting junctional conductance (Oh S et al. Neuron, 1997 Oct;19:927-38; Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 102 of the GJB1 protein (p.Glu102Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8004109, 14627639, 17353473, 25614874). ClinVar contains an entry for this variant (Variation ID: 216038). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9354338, 9469571, 9592087, 14627639). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 28, 2023

The GJB1 c.305A>G; p.Glu102Gly variant (rs779696968) is described in the literature in individuals and families with Charcot-Marie-Tooth (CMT) and is reported as a frequently detected variant in individuals with CMT (Cortese 2020, DiVincenzo 2014, Ionasescu 1994). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 216038) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved computational analyses predict that this variant is deleterious (REVEL: 0.877). In support of this prediction, functional studies show this variant alters the voltage-gating, resulting in increased sensitivity to intracellular acidification (Abrams 2003, Ressot 1998). Based on available information, this variant is classified as pathogenic. References: Abrams CK et al Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J Neurosci. 2003 Nov 19;23(33):10548-58. PMID: 14627639. Cortese A et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology. 2020 Jan 7;94(1):e51-e61. PMID: 31827005. DiVincenzo C et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9. PMID: 25614874. Ionasescu V et al. Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum Mol Genet. 1994 Feb;3(2):355-8. 8004109. Ressot C et al. Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci. 1998 Jun 1;18(11):4063-75. PMID: 9592087 -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D;.;D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;.;D;.;D
Sift4G	Uncertain	0.0030	D;.;D;.;D
Polyphen		0.96	D;D;D;D;D
Vest4		0.80
MutPred		0.84		Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);
MVP		1.0
MPC		1.6
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.71
gMVP		0.98

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: rs779696968; hg19: chrX-70443862;