rs104894822

Variant names:

• chrX-71224321-A-G
• rs104894822
• NM_000166.6:c.614A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-71224321-A-G
• chrX-71224321-A-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.614A>G​(p.Asn205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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. N205I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.31
• Publications: 18 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 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, 0.955
• PP5: Variant X-71224321-A-G is Pathogenic according to our data. Variant chrX-71224321-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10442.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.614A>G	p.Asn205Ser	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.614A>G	p.Asn205Ser	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.614A>G	p.Asn205Ser	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.614A>G	p.Asn205Ser	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2 Other:1

Feb 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.614A>G(p.Asn205Ser) variant in GJB1 gene has been reported previously in X-linked state in individual(s) affected with X-linked Charcot-Marie-Tooth (CMTX) disease (Milley et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Asn at position 205 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn205Ser in GJB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Damaging, SIFT - Tolerated, and MutationTaster - Disease causing automatic) predicts conflicting evidence on protein structure and function for this variant. This variant is located in a mutational hot spot and/or a critical and well-established functional domain. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Aug 15, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/201577 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Results on protein functions were conflicting. Moderate co-segregation with disease in affected individuals from a single family. -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB1: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the GJB1 protein (p.Asn205Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMTX) (PMID: 9401007, 9452099, 10071100, 12497641, 19259128, 24327141, 27544631, 28469099). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10442). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;.;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
PhyloP100		9.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;.;D;.;D
REVEL	Pathogenic	0.76
Sift	Benign	0.065	T;.;T;.;T
Sift4G	Benign	0.073	T;.;T;.;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.92
MutPred		0.78		Loss of MoRF binding (P = 0.1707);Loss of MoRF binding (P = 0.1707);Loss of MoRF binding (P = 0.1707);Loss of MoRF binding (P = 0.1707);Loss of MoRF binding (P = 0.1707);
MVP		0.97
MPC		1.7
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.99
Mutation Taster		=7/93	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: rs104894822; hg19: chrX-70444171;