rs863224974

chrX-71223751-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):c.44G>A(p.Arg15Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,733 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.83

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 18 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-71223751-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1709368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant X-71223751-G-A is Pathogenic according to our data. Variant chrX-71223751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223751-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.44G>A	p.Arg15Gln	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.44G>A	p.Arg15Gln	missense_variant	2/2
GJB1	XM_011530907.3	c.44G>A	p.Arg15Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.44G>A	p.Arg15Gln	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096733 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362117

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.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 11, 2022	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2022	Published functional studies demonstrate no affect on the expression and localization of the protein, but do show a moderate effect of the channel conductance (Shy et al., 2007; Deschenes et al., 1997; Abrams et al., 2001); The majority of missense variants in this gene are considered pathogenic; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9364054, 28448691, 19062535, 15006706, 28768847, 17353473, 11325342, 22159091, 10586261, 27098783, 28286897, 31827005, 32010055, 11718056, 32376792, 8162049) -

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jul 27, 2023	ACMG criteria used to clasify this variant: PS3, PP3_STR, PM1, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 22, 2023	The GJB1 c.44G>A variant is classified a PATHOGENIC variant (PS4, PS3_moderate, PM2, PM5_supporting, PP3) The variant is a single nucleotide change in exon 2/2 of the GJB1 gene, which is predicted to change the amino acid arginine at position 15 in the protein to glutamine. The variant is in dbSNP (rs863224974) but is absent from population databases (PM2). The variant has been reported multiple times in unrelated individuals with clinical phenotype of CMT (PMID:8162049, 28286897, 32010055) (PS4). Functional studies have demonstrated that the variant has no effect on protein localization and channel formation but does show moderate effect on channel conductance (PMID: 9364054, 11325342, 15006706) (PS3_moderate). Other missense changes at the same amino acid residue have been previously reported and classified as pathogenic/ like pathogenic (i.e. p.R15W, p.R15P) (PM5_supporting). This variant has been reported in ClinVar (Variation ID: 217169) or HGMD (Accession no.: CM940828) as Pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2020

The p.R15Q variant (also known as c.44G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 44. The arginine at codon 15 is replaced by glutamine, an amino acid with highly similar properties. This variant has been frequently reported in individuals with features consistent with X-linked Charcot-Marie-Tooth disease type 1 and has been shown to co-segregate with disease (Capasso M et al. Clin Neurophysiol, 2004 Jan;115:64-70; Fairweather N et al. Hum Mol Genet, 1994 Jan;3:29-34; Sun B et al. Chin Med J (Engl), 2016 May;129:1011-6; Niu J et al. Front Neurol, 2019 Jan;10:1406). Functional studies of this variant have demonstrated proper protein localization and channel formation but some altered channel activity (Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70). Another alteration at this position (p.R15W) has also been reported in multiple patients with features of Charcot-Marie-Tooth disease (Wicklein EM et al. J Neurol Neurosurg Psychiatry, 1997 Sep;63:379-81; Senderek J et al. J Neurol Sci, 1999 Aug;167:90-101). The p.R15Q (c.44G>A) variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 15 of the GJB1 protein (p.Arg15Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT (PMID: 8162049, 10586261, 11718056, 14706470, 15719046, 17353473, 18379723, 19062535, 22464564). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217169). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 11325342, 15006706). This variant disrupts the p.Arg15 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9328258, 10093067, 10639608, 11325342, 24078732). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D;D;D;T;.;D
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.77	N;N;N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;.;N;.;N;.;N
REVEL	Pathogenic	0.82
Sift	Benign	0.062	T;.;T;.;T;.;T
Sift4G	Benign	0.094	T;.;T;.;T;.;T
Polyphen		0.99	D;D;D;D;.;.;D
Vest4		0.78
MutPred		0.85		Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);
MVP		0.99
MPC		1.8
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.95

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: rs863224974; hg19: chrX-70443601;