rs771022595

Positions:

• chrX-71224247-C-G
• chrX-71224247-C-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.540C>G​(p.Phe180Leu) variant causes a missense change involving the alteration of a non-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: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 0.292

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, 0.991
• PP5: Variant X-71224247-C-G is Pathogenic according to our data. Variant chrX-71224247-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 578250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224247-C-G is described in Lovd as [Pathogenic]. Variant chrX-71224247-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.540C>G	p.Phe180Leu	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.540C>G	p.Phe180Leu	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.540C>G	p.Phe180Leu	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.540C>G	p.Phe180Leu	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/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2023	A different nucleotide change resulting in the same missense variant (c.538 T>C p.F180L) has been reported in association with CMTX1 in published literature (Park et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16922730) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 22, 2019	Not found in the total gnomAD dataset, and the data is high quality (0/195627 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in a likely critical domain of the protein. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 180 of the GJB1 protein (p.Phe180Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe180 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 10873293), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 578250). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 16922730, 28448691; Invitae; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

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	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;D;D;D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;.;.;.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.1	D;.;D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.0030	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.94
MutPred		0.89		Loss of glycosylation at S182 (P = 0.2194);Loss of glycosylation at S182 (P = 0.2194);Loss of glycosylation at S182 (P = 0.2194);Loss of glycosylation at S182 (P = 0.2194);Loss of glycosylation at S182 (P = 0.2194);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		-3.4
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: rs771022595; hg19: chrX-70444097;