chrX-71224221-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000166.6(GJB1):​c.514C>T​(p.Pro172Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P172R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

GJB1
NM_000166.6 missense

Scores

14
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.90
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 17 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-71224221-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637168.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant X-71224221-C-T is Pathogenic according to our data. Variant chrX-71224221-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224221-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJB1NM_000166.6 linkc.514C>T p.Pro172Ser missense_variant Exon 2 of 2 ENST00000361726.7 NP_000157.1 P08034A0A654ICJ7
GJB1NM_001097642.3 linkc.514C>T p.Pro172Ser missense_variant Exon 2 of 2 NP_001091111.1 P08034A0A654ICJ7
GJB1XM_011530907.3 linkc.514C>T p.Pro172Ser missense_variant Exon 2 of 2 XP_011529209.1 P08034A0A654ICJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJB1ENST00000361726.7 linkc.514C>T p.Pro172Ser missense_variant Exon 2 of 2 1 NM_000166.6 ENSP00000354900.6 P08034

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.00000566
AC:
1
AN:
176561
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
62163
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000547
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Jul 10, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in an affected male with Charcot-Marie-Tooth disease; however, no further clinical or segregation information was provided (PMID: 8266101); Published function studies showed discordant results (PMID: 9592087, 15006706); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34750751, 17353473, 21297078, 22342665, 9592087, 15006706, 9856562, 21692908, 8266101) -

May 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Oct 20, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 172 of the GJB1 protein (p.Pro172Ser). This variant is present in population databases (rs104894811, gnomAD 0.005%). This missense change has been observed in individuals with CMTX (PMID: 8266101, 17353473, 21692908). ClinVar contains an entry for this variant (Variation ID: 10432). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 9592087, 15006706). This variant disrupts the p.Pro172 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9633821, 9856562, 21692908, 27098783). 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. -

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1
Dec 24, 1993
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.82
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;D;D;D;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
1.0
.;.;.;.;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H;H;H;H;H
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-7.8
D;.;D;.;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.;D;.;D
Sift4G
Pathogenic
0.0
D;.;D;.;D
Polyphen
1.0
D;D;D;D;D
Vest4
0.30
MutPred
0.82
Loss of ubiquitination at K167 (P = 0.2432);Loss of ubiquitination at K167 (P = 0.2432);Loss of ubiquitination at K167 (P = 0.2432);Loss of ubiquitination at K167 (P = 0.2432);Loss of ubiquitination at K167 (P = 0.2432);
MVP
1.0
MPC
1.9
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894811; hg19: chrX-70444071; API