chrX-71223930-C-T

Variant names:

• chrX-71223930-C-T
• rs116840819
• NM_000166.6:c.223C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.223C>T​(p.Arg75Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001158504: Functional analyses of the variant protein in cell culture and transgenic mice show that the p.Arg75Trw variant causes defects in GJB1 protein function consistent with known CMT disease mechanisms (Sargiannidou 2009, Abrams 2013)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 4.92
• Publications: 41 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001158504: Functional analyses of the variant protein in cell culture and transgenic mice show that the p.Arg75Trw variant causes defects in GJB1 protein function consistent with known CMT disease mechanisms (Sargiannidou 2009, Abrams 2013).; SCV000293446: "Published functional studies demonstrate a damaging effect on the gene product" (PMID: 12460545, 23209285); SCV001880849: Studies showed defective protein activity and transgenic mice with a demyelating neuropathy (PMID: 12460545, 19369543, 23209285, 28334782).; SCV000776746: Experimental studies have shown that this missense change affects GJB1 function (PMID: 12460545, 19369543, 23209285).; SCV002727953: Functional studies indicate this alteration impairs gap junction formation and transgenic mice expressing this alteration recapitulate the phenotype (Kagiava A et al. Hum Mol Genet, 2018 04;27:1460-1473; Kyriakoudi S et al. Hum Mol Genet, 2017 05;26:1622-1633; Abrams CK et al. J Biol Chem, 2013 Feb;288:3609-19; Sargiannidou I et al. J Neurosci, 2009 Apr;29:4736-49).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 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-71223931-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-71223930-C-T is Pathogenic according to our data. Variant chrX-71223930-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21082.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.223C>T	p.Arg75Trp	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.223C>T	p.Arg75Trp	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.223C>T	p.Arg75Trp	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.223C>T	p.Arg75Trp	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1092506 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 358516

African (AFR) AF: 0.00 AC: 0 AN: 26332

American (AMR) AF: 0.00 AC: 0 AN: 34449

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19289

East Asian (EAS) AF: 0.00 AC: 0 AN: 30056

South Asian (SAS) AF: 0.00 AC: 0 AN: 53213

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838964

Other (OTH) AF: 0.00 AC: 0 AN: 45893

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000261 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely 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 (3)
-	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	0.87
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.99		Gain of helix (P = 0.0696)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116840819; hg19: chrX-70443780;