rs1131691322

chrX-71224014-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000166.6(GJB1):c.307A>G(p.Lys103Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K103K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 7.57

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 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant X-71224014-A-G is Pathogenic according to our data. Variant chrX-71224014-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224014-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.307A>G	p.Lys103Glu	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.307A>G	p.Lys103Glu	missense_variant	2/2
GJB1	XM_011530907.3	c.307A>G	p.Lys103Glu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.307A>G	p.Lys103Glu	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090022 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 356438

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429329). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 21692908; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 103 of the GJB1 protein (p.Lys103Glu). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2017

A variant that is likely pathogenic has been identified in the GJB1 gene. The K103E variant has beenreported in several unrelated individuals with CMTX1 (Bone et al., 1997; Siskind et al., 2011). TheK103E variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The K103E variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function.Missense variants in nearby residues have been reported in the Human Gene Mutation Database inassociation with CMTX1 (Stenson et al., 2014), supporting the functional importance of this regionof the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benigncannot be excluded. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Benign	0.91
DEOGEN2	Pathogenic	0.87	D;D;D;D;D
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	0.94	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D;.;D;.;D
REVEL	Pathogenic	0.78
Sift	Benign	0.19	T;.;T;.;T
Sift4G	Benign	0.44	T;.;T;.;T
Polyphen		0.12	B;B;B;B;B
Vest4		0.84
MutPred		0.81		Loss of ubiquitination at K103 (P = 0.0412);Loss of ubiquitination at K103 (P = 0.0412);Loss of ubiquitination at K103 (P = 0.0412);Loss of ubiquitination at K103 (P = 0.0412);Loss of ubiquitination at K103 (P = 0.0412);
MVP		1.0
MPC		1.9
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.99

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: rs1131691322; hg19: chrX-70443864;