rs1555936999

Positions:

• chrX-71223741-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000166.6(GJB1):​c.34G>A​(p.Gly12Ser) 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.97

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 10 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, 0.981
• PP5: Variant X-71223741-G-A is Pathogenic according to our data. Variant chrX-71223741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 477595.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71223741-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.34G>A	p.Gly12Ser	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.34G>A	p.Gly12Ser	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.34G>A	p.Gly12Ser	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.34G>A	p.Gly12Ser	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2017

This sequence change replaces glycine with serine at codon 12 of the GJB1 protein (p.Gly12Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with Charcot-Marie-Tooth disease, type X (PMID: 8266101). Experimental studies have shown that this missense change alters the structure of the GJB1 (also known as Cx32) protein such that a functional channel is not formed and the mutant protein is mislocalized to the Golgi apparatus instead of the plasma membrane (PMID: 9354338, 11325342, 15006706, 19638273, 9364054, 10646523, 22705201). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;.;.;.;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.;.;M
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.5	D;.;D;.;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;.;D;.;D;.;D
Sift4G	Uncertain	0.039	D;.;D;.;T;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.91
MutPred		0.92		Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);Loss of glycosylation at S11 (P = 0.0326);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.98

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: rs1555936999; hg19: chrX-70443591;