chrX-71223790-T-C

Position:

• chrX-71223790-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000166.6(GJB1):​c.83T>C​(p.Ile28Thr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I28N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.99

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 11 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-71223790-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215983.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-71223790-T-C is Pathogenic according to our data. Variant chrX-71223790-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246094.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chrX-71223790-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.83T>C	p.Ile28Thr	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.83T>C	p.Ile28Thr	missense_variant	2/2
GJB1	XM_011530907.3	c.83T>C	p.Ile28Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.83T>C	p.Ile28Thr	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2016

A published I28T variant that is likely pathogenic has been identified in the GJB1 gene. The I28T variant has beenreported previously in individuals with Charcot-Marie-Tooth neuropathy (CMT) (Bone et al., 1997; Nicholson et al.,1998). It was not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I28Tvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where aminoacids with similar properties to Isoleucine are tolerated across species. It is predicted to occur within the firsttransmembrane domain of the GJB1 protein, and a different missense variant in the same codon (I28N) as well asmultiple missense variants in nearby residues have been reported in the Human Gene Mutation Database inassociation with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Insilico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant islikely pathogenic; however, the possibility that it is benign cannot be excluded. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2019

This variant disrupts the p.Ile28 amino acid residue in GJB1. Other variant(s) that disrupt this residue (p.Ile28Asn) have been determined to be pathogenic (PMID: 9361298, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with clinical features of Charcot-Marie-Tooth disease (PMID: 9818870). ClinVar contains an entry for this variant (Variation ID: 246094). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 28 of the GJB1 protein (p.Ile28Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L;L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	D;.;D;.;D;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.;D;.;D;.;D
Sift4G	Uncertain	0.0020	D;.;D;.;T;.;D
Polyphen		0.87	P;P;P;P;.;.;P
Vest4		0.83
MutPred		0.94		Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);Loss of stability (P = 0.0091);
MVP		1.0
MPC		1.4
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.64
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: rs768834663; hg19: chrX-70443640;