rs879254012

Variant names:

• chrX-71223819-G-A
• rs879254012
• NM_000166.6:c.112G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.112G>A​(p.Val38Met) 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. 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. V38G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 4.42
• Publications: 10 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 19 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 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-71223820-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216292.
• 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, 0.977
• PP5: Variant X-71223819-G-A is Pathogenic according to our data. Variant chrX-71223819-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 245946.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.112G>A	p.Val38Met	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.112G>A	p.Val38Met	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.112G>A	p.Val38Met	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.112G>A	p.Val38Met	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Sep 19, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V38M variant in the GJB1 gene has been reported previously in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014). The V38M mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V38M mutation is a conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Valine are tolerated across species. A functional study showed that the V38M mutation alters conductance-voltage relation that would likely impact channel function, and an additional study showed that protein with the V38M variant was located in the Golgi apparatus rather than at the cell membrane (Oh et al., 1997; Yum et al., 2002). -

Dec 26, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val38Met was first reported in a single family with X-linked dominant Charcot-Marie-Tooth neuropathy (CMT), where the variant was demonstrated to segregate with disease (Orth 1994). This variant is in the first transmembrane domain of the GJB1 channel, and functional studies of the variant protein showed altered conductance-voltage compared to WT suggestive of channel closure (Oh 1998). Variants that change codon 38 to a different amino acid and others nearby have been reported in association with CMT (Hong 2017, Karadima 2004). The p.Val38Met is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) and has been reported to the ClinVar database with a pathogenic classification (Variation ID: 245946). Altogether the p.Val38Met variant is considered to be pathogenic. -

May 30, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PM1, PM2, PM5, PS3 -

Jan 18, 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 was not reported in large, multi-ethnic, general populations. (http://gnomad.broadinstitute.org) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12460545, 9354338) -

Inborn genetic diseases Pathogenic:1

Jan 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112G>A (p.V38M) alteration is located in exon 2 (coding exon 1) of the GJB1 gene. This alteration results from a G to A substitution at nucleotide position 112, causing the valine (V) at amino acid position 38 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in multiple individuals of a family with X-linked Charcot-Marie-Tooth disease and found to co-segregate with disease (Orth, 1994; Gal, 1985). This amino acid position is well conserved in available vertebrate species. In an assay testing GJB1 function, this variant showed a functionally abnormal result (Oh,1997; Yum, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 38 of the GJB1 protein (p.Val38Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked dominant Charcot-Marie-Tooth disease (PMID: 7833935). ClinVar contains an entry for this variant (Variation ID: 245946). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9354338, 12460545). This variant disrupts the p.Val38 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 14991359, 28448691), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;M;M;.;.;M
PhyloP100		4.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D;.;D;.;D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D;.;D;.;D
Sift4G	Uncertain	0.0040	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.81
MutPred		0.89		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97
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: rs879254012; hg19: chrX-70443669;