X-71224026-C-T

Variant names:

• chrX-71224026-C-T
• rs863224973
• NM_000166.6:c.319C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 19P and 4B. PS3 PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong BS2

The NM_000166.6(GJB1):​c.319C>T​(p.Arg107Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000334 in 1,199,193 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes 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: "SCV006103083: The variant results in <10% of normal functional conductance activity (Wang_2004). PMID:8829637, 15006706, 9272161" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.220
• Publications: 13 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006103083: The variant results in <10% of normal functional conductance activity (Wang_2004). PMID: 8829637, 15006706, 9272161; SCV001207843: Experimental studies have shown that this missense change affects GJB1 function (PMID: 15006706).; SCV004022733: Published functional studies demonstrate a damaging effect showing that R107W formed defective junctional channels (Wang et al., 2004); PMID:30042657, 27544631, 19259128, 10737979, 9401007, 9272161, 8829637, 32010055, 9018031, 25429913, 12067629, 18937943, 33314704, 22464564, 31827005, 32376792, 37284795, 15006706
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000166.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71224027-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1299490.
• 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, 0.881
• PP5: Variant X-71224026-C-T is Pathogenic according to our data. Variant chrX-71224026-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.319C>T	p.Arg107Trp	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.319C>T	p.Arg107Trp	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.319C>T	p.Arg107Trp	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.319C>T	p.Arg107Trp	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.319C>T	p.Arg107Trp	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.319C>T	p.Arg107Trp	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111472 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

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087721 Hom.: 0 Cov.: 31 AF XY: 0.00000564 AC XY: 2 AN XY: 354675

African (AFR) AF: 0.00 AC: 0 AN: 26284

American (AMR) AF: 0.00 AC: 0 AN: 34575

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18836

East Asian (EAS) AF: 0.00 AC: 0 AN: 30029

South Asian (SAS) AF: 0.00 AC: 0 AN: 52171

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.00000359 AC: 3 AN: 835996

Other (OTH) AF: 0.00 AC: 0 AN: 45657

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111472 Hom.: 0 Cov.: 22 AF XY: 0.0000297 AC XY: 1 AN XY: 33656

African (AFR) AF: 0.00 AC: 0 AN: 30685

American (AMR) AF: 0.00 AC: 0 AN: 10469

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53019

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.0000800 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (4)
3	-	-	not provided (3)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.22
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.76		Loss of disorder (P = 0.0046)
MVP		1.0
MPC		1.7
ClinPred		0.94	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.96
Mutation Taster		=85/15	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: rs863224973; hg19: chrX-70443876; COSMIC: COSV100661259; COSMIC: COSV100661259;