rs104894812

Positions:

• chrX-71224122-G-A

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.415G>A​(p.Val139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,662 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 (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 U:1 O:1
• Conservation: PhyloP100: 2.65

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 chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant X-71224122-G-A is Pathogenic according to our data. Variant chrX-71224122-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224122-G-A is described in Lovd as [Pathogenic]. Variant chrX-71224122-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.415G>A	p.Val139Met	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.415G>A	p.Val139Met	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.415G>A	p.Val139Met	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.415G>A	p.Val139Met	missense_variant	2/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000584 AC: 1 AN: 171137 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 57039

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 358430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1995	- -
Pathogenic, criteria provided, single submitter	research	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo	Jul 20, 2021	3. The p.Val139Met variant in GJB1 has been reported in several families worldwide with Charcot-Marie-Tooth Neuropathy X linked. ClinVar classifies this variant as Pathogenic (Variation ID:10433), 1 star (criteria provided, 4 submissions), citing 7 articles (12402337, 11325342, 9364054, 9272161, 8816997 and 2 more). This variant is in a hotspot region and an important functional domain of the protein (M3). Besides that, this variant segregates with family phenotype. In summary, the p.Val139Met meets our criteria to be classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2023	PP1_strong, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	GJB1: PP1:Strong, PM2, PM5, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2024	Published functional studies demonstrate this variant exhibits no GJIC capacity function, it demonstrates dominant negative down-regulation of GJIC function when co-expressed with wild type, and it alters the formation and structure of gap junction plaques (PMID: 8816997, 28071741); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23279425, 11325342, 9364054, 18714809, 7477983, 10093067, 9099841, 10586284, 11438991, 12477701, 8266101, 28071741, 8800924, 10586261, 12402337, 9820654, 34326750, 32376792, 30340945, 8816997, 9272161) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2021

The p.V139M pathogenic mutation (also known as c.415G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 415. The valine at codon 139 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), and it has been found to segregate with CMTX1 in multiple families (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35; Halbrich M et al. Can J Neurol Sci, 2008 Jul;35:372-4; Hoebeke C et al. Arch Pediatr, 2018 Nov;25:452-458; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Silander K et al. Hum Genet, 1997 Sep;100:391-7). Functional studies indicate that this alteration impairs gap junction formation and results in altered pattern of trafficking and localization (Omori Y et al. Mol Biol Cell, 1996 Jun;7:907-16; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Abrams CK et al. Sci Rep, 2017 01;7:40166). 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 139 of the GJB1 protein (p.Val139Met). 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 Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9272161, 9364054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10433). 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: 8816997, 11325342). For these reasons, this variant has been classified as Pathogenic. -

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	0.61
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;D;D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	.;.;.;.;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.010	N;.;N;.;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.0040	D;.;D;.;D
Polyphen		0.99	D;D;D;D;D
Vest4		0.58
MutPred		0.86		Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);
MVP		0.98
MPC		1.6
ClinPred		0.69	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.95

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: rs104894812; hg19: chrX-70443972;