rs587777878

chrX-71224287-A-G

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.580A>G(p.Met194Val) 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. M194L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant X-71224287-A-G is Pathogenic according to our data. Variant chrX-71224287-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 155725.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71224287-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.580A>G	p.Met194Val	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.580A>G	p.Met194Val	missense_variant	2/2
GJB1	XM_011530907.3	c.580A>G	p.Met194Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.580A>G	p.Met194Val	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met194 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 27544631), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 155725). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 9272161, 25802885). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 194 of the GJB1 protein (p.Met194Val). -

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

Pathogenic, no assertion criteria provided

literature only

Northcott Neuroscience Laboratory, ANZAC Research Institute

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;D;D;D;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D;.;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.014	D;.;D;.;D
Sift4G	Uncertain	0.0090	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.92
MutPred		0.74		Gain of catalytic residue at M194 (P = 0.0645);Gain of catalytic residue at M194 (P = 0.0645);Gain of catalytic residue at M194 (P = 0.0645);Gain of catalytic residue at M194 (P = 0.0645);Gain of catalytic residue at M194 (P = 0.0645);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
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: rs587777878; hg19: chrX-70444137;