NM_000166.6:c.305A>G

Variant names:

• chrX-71224012-A-G
• rs779696968
• NM_000166.6:c.305A>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM2 PP2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000253767: Experimental studies have shown that this missense change affects GJB1 function (PMID:9354338, 9469571, 9592087, 14627639)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102D) 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:7 U:1
• Conservation: PhyloP100: 7.34
• Publications: 17 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000253767: Experimental studies have shown that this missense change affects GJB1 function (PMID: 9354338, 9469571, 9592087, 14627639).; SCV000329359: 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); SCV000613484: "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, PMID:14627639; SCV002754074: 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).; SCV004563416: "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)." PMID: 14627639. PMID: 9592087; SCV006074078: Two publications reported experimental evidence evaluating an impact on protein function and this variant affected the GJB1 protein function (Oh_1997, Ressot_1998). PMID: 10873293, 9354338, 37284795, 9592087
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• 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 VariationId is 216038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.305A>G	p.Glu102Gly	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.305A>G	p.Glu102Gly	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.305A>G	p.Glu102Gly	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.305A>G	p.Glu102Gly	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.305A>G	p.Glu102Gly	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.305A>G	p.Glu102Gly	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

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

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

GnomAD2 exomes AF: 0.0000118 AC: 2 AN: 169210 AF XY: 0.0000181

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 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

African (AFR) AF: 0.00 AC: 0 AN: 30596

American (AMR) AF: 0.00 AC: 0 AN: 10461

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3497

South Asian (SAS) AF: 0.00 AC: 0 AN: 2627

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52948

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (2)
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.80
MutPred		0.84		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
Mutation Taster		=36/64	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: rs779696968; hg19: chrX-70443862;