rs863224612

Positions:

• chrX-71223820-T-C
• chrX-71223820-T-G

Variant summary

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

The ENST00000361726.7(GJB1):​c.113T>C​(p.Val38Ala) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V38G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 ENST00000361726.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.24

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, 16 uncertain in ENST00000361726.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71223819-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-71223820-T-C is Pathogenic according to our data. Variant chrX-71223820-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637179.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71223820-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.113T>C	p.Val38Ala	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.113T>C	p.Val38Ala	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.113T>C	p.Val38Ala	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.113T>C	p.Val38Ala	missense_variant	2/2	1	NM_000166.6	ENSP00000354900	P1

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

Dec 02, 2021

This variant disrupts the p.Val38 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7833935, 9354338, 12460545; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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"). ClinVar contains an entry for this variant (Variation ID: 637179). This missense change has been observed in individuals with Charcot-Marie-Tooth disease and/or clinical features of Charcot-Marie-Tooth disease (PMID: 14991359, 32010055; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 38 of the GJB1 protein (p.Val38Ala). -

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	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	.;.;.;.;T;T;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;L;L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;.;D;.;D;.;D
REVEL	Pathogenic	0.83
Sift	Benign	0.085	T;.;T;.;T;.;T
Sift4G	Benign	0.31	T;.;T;.;T;.;T
Polyphen		0.30	B;B;B;B;.;.;B
Vest4		0.81
MutPred		0.90		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.99
MPC		1.1
ClinPred		0.93	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.62
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: rs863224612; hg19: chrX-70443670;