rs104894822

Positions:

• chrX-71224321-A-G
• chrX-71224321-A-T

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.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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.31

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, 0.955
• PP5: Variant X-71224321-A-G is Pathogenic according to our data. Variant chrX-71224321-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224321-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.614A>G	p.Asn205Ser	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.614A>G	p.Asn205Ser	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.614A>G	p.Asn205Ser	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.614A>G	p.Asn205Ser	missense_variant	2/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GJB1: PP1:Strong, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2019	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. -

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

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). 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%. 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
MutationTaster	Benign	1.0	A;A;A
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

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: rs104894822; hg19: chrX-70444171;