NM_000166.6:c.116C>T

Variant names:

• chrX-71223823-C-T
• rs786204095
• NM_000166.6:c.116C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.116C>T​(p.Ala39Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,971 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A39P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.86
• Publications: 15 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 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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, 0.992
• PP5: Variant X-71223823-C-T is Pathogenic according to our data. Variant chrX-71223823-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188136.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.116C>T	p.Ala39Val	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.116C>T	p.Ala39Val	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.116C>T	p.Ala39Val	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097971 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363343

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841892

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 13, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Oct 07, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Because this sequence change is absent from the general population, has been observed in four independent CMT case reports, and disrupts the function of the GJB1 gene product, it has been classified as Pathogenic. This sequence change causes mislocalization of the protein product in the cells. Functional studies showed that the wild type protein is targeted to the cell membrane whereas the mutant protein is localized to the endoplasmic reticulum and therefore interferes with the formation of gap junctions (PMID: 12111842). This sequence change has been reported in patients and families affected with CMT (PMID:  9888385, 12457340, 10400511, 10521546) and is not present in population databases. This sequence change replaces alanine with valine at codon 39 of the GJB1 protein (p.Ala39Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

not provided Pathogenic:1

Feb 08, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12111842, 28334782) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M;M;.;.;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;.;D;.;D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;T;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.92
MutPred		0.97		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.99
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: rs786204095; hg19: chrX-70443673;