X-71223784-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000166.6(GJB1):c.77C>G(p.Ser26Trp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S26L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.88

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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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-71223784-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 155726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-71223784-C-G is Pathogenic according to our data. Variant chrX-71223784-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 477604.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71223784-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.77C>G	p.Ser26Trp	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.77C>G	p.Ser26Trp	missense_variant	2/2
GJB1	XM_011530907.3	c.77C>G	p.Ser26Trp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.77C>G	p.Ser26Trp	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2019

For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Ser26Leu) has been determined to be pathogenic (PMID: 8990008, 25429913, 9354338, 25802885). This suggests that the serine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change alters channel gating but does not significantly alter channel conductance (PMID: 25969535). This variant has been reported to segregate with X-linked Charcot-Marie-Tooth disease in 4 related families and is considered a founder mutation in French-Canadian population (PMID: 11252295). This variant has also been reported in an individual affected with severe Charcot-Marie-Tooth disease (PMID: 11437164). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with tryptophan at codon 26 of the GJB1 protein (p.Ser26Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H;H;H;.;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.3	D;.;D;.;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.82
MutPred		0.93		Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);Gain of MoRF binding (P = 0.0462);
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		1.0

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: rs587777876; hg19: chrX-70443634;