This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly compromised plasma membrane localization and failed to form functional channels (PMID: 27844031, 7946361, 9364054).
ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.556G>A (p.Glu186Lys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000166.6(GJB1):c.556G>A (p.Glu186Lys)
Variation ID: 21086 Accession: VCV000021086.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq13.1 X: 71224263 (GRCh38) [ NCBI UCSC ] X: 70444113 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 Oct 24, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000166.6:c.556G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Glu186Lys missense NM_001097642.3:c.556G>A NP_001091111.1:p.Glu186Lys missense NC_000023.11:g.71224263G>A NC_000023.10:g.70444113G>A NG_008357.1:g.14052G>A LRG_245:g.14052G>A LRG_245t1:c.556G>A LRG_245p1:p.Glu186Lys LRG_245t2:c.556G>A LRG_245p2:p.Glu186Lys P08034:p.Glu186Lys - Protein change
- E186K
- Other names
- -
- Canonical SPDI
- NC_000023.11:71224262:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GJB1 | - | - |
GRCh38 GRCh37 |
795 | 927 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 24, 2023 | RCV000020176.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 22, 2023 | RCV000654837.9 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000789812.2 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 24, 2023 | RCV001815168.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 27, 2021 | RCV002345250.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516475.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(Dec 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002771556.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly compromised plasma membrane localization and failed to form functional channels (PMID: 27844031, 7946361, 9364054). (less)
|
|
|
Pathogenic
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004170535.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); 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; This variant is associated with the following publications: (PMID: 22243284, 9364054, 10848620, 8266101, 27844031, 31211173, 10737979, 32376792, 12542510, 7946361) (less)
|
|
|
Pathogenic
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244639.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PS4, PM2, PP3
|
|
|
Pathogenic
(Apr 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth Neuropathy X
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000776739.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). 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. ClinVar contains an entry for this variant (Variation ID: 21086). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the GJB1 protein (p.Glu186Lys). (less)
|
|
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Pathogenic
(Aug 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002653038.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at … (more)
The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Liu X et al. Front Neurol, 2020 Jul;11:690; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Takashima H et al. Acta Neurol Scand, 2003 Jan;107:31-7; Dubourg O et al. Brain, 2001 Oct;124:1958-67). In addition, this mutation has been reported to segregate with CMTX1 in one family (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35). Functional studies indicate that the E186K alteration impairs localization and channel function (Matsuyama W et al. J Hum Genet, 2001;46:307-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Vanslyke JK et al. Mol Biol Cell, 2009 May;20:2451-63; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063330.20
First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000929196.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040507.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); 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; This variant is associated with the following publications: (PMID: 22243284, 9364054, 10848620, 8266101, 27844031, 31211173, 10737979, 32376792, 12542510, 7946361)
Comment:
PS3, PS4, PM2, PP3
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). 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. ClinVar contains an entry for this variant (Variation ID: 21086). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the GJB1 protein (p.Glu186Lys).
Comment:
The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Liu X et al. Front Neurol, 2020 Jul;11:690; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Takashima H et al. Acta Neurol Scand, 2003 Jan;107:31-7; Dubourg O et al. Brain, 2001 Oct;124:1958-67). In addition, this mutation has been reported to segregate with CMTX1 in one family (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35). Functional studies indicate that the E186K alteration impairs localization and channel function (Matsuyama W et al. J Hum Genet, 2001;46:307-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Vanslyke JK et al. Mol Biol Cell, 2009 May;20:2451-63; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly compromised plasma membrane localization and failed to form functional channels (PMID: 27844031, 7946361, 9364054).
Comment:
Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); 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; This variant is associated with the following publications: (PMID: 22243284, 9364054, 10848620, 8266101, 27844031, 31211173, 10737979, 32376792, 12542510, 7946361)
Comment:
PS3, PS4, PM2, PP3
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). 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. ClinVar contains an entry for this variant (Variation ID: 21086). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the GJB1 protein (p.Glu186Lys).
Comment:
The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Liu X et al. Front Neurol, 2020 Jul;11:690; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Takashima H et al. Acta Neurol Scand, 2003 Jan;107:31-7; Dubourg O et al. Brain, 2001 Oct;124:1958-67). In addition, this mutation has been reported to segregate with CMTX1 in one family (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35). Functional studies indicate that the E186K alteration impairs localization and channel function (Matsuyama W et al. J Hum Genet, 2001;46:307-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Vanslyke JK et al. Mol Biol Cell, 2009 May;20:2451-63; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. | Adam MP | - | 2024 | PMID: 20301548 |
| Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations. | Liu X | Frontiers in neurology | 2020 | PMID: 32903794 |
| Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. | Hsu YH | Annals of clinical and translational neurology | 2019 | PMID: 31211173 |
| Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. | Lu YY | Chinese medical journal | 2017 | PMID: 28469099 |
| Clinical characterization and genetic analysis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1. | Hong YB | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28448691 |
| Clinical and biophysical characterization of 19 GJB1 mutations. | Tsai PC | Annals of clinical and translational neurology | 2016 | PMID: 27844031 |
| Mutational analysis of PMP22, GJB1 and MPZ in Greek Charcot-Marie-Tooth type 1 neuropathy patients. | Karadima G | Clinical genetics | 2011 | PMID: 22243284 |
| Conformational maturation and post-ER multisubunit assembly of gap junction proteins. | Vanslyke JK | Molecular biology of the cell | 2009 | PMID: 19297523 |
| CMT1X phenotypes represent loss of GJB1 gene function. | Shy ME | Neurology | 2007 | PMID: 17353473 |
| Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. | Takashima H | Acta neurologica Scandinavica | 2003 | PMID: 12542510 |
| Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. | Dubourg O | Brain : a journal of neurology | 2001 | PMID: 11571214 |
| Phenotypes of X-linked Charcot-Marie-Tooth disease and altered trafficking of mutant connexin 32 (GJB1). | Matsuyama W | Journal of human genetics | 2001 | PMID: 11393532 |
| Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. | VanSlyke JK | Molecular biology of the cell | 2000 | PMID: 10848620 |
| Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. | Mersiyanova IV | Human mutation | 2000 | PMID: 10737979 |
| 3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands. | - | Neuromuscular disorders : NMD | 1998 | PMID: 10093067 |
| Altered trafficking of mutant connexin32. | Deschênes SM | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1997 | PMID: 9364054 |
| New mutations in the X-linked form of Charcot-Marie-Tooth disease. | Latour P | European neurology | 1997 | PMID: 9018031 |
| Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy. | Fain PR | American journal of human genetics | 1994 | PMID: 8304339 |
| Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease. | Bruzzone R | Neuron | 1994 | PMID: 7946361 |
| Connexin mutations in X-linked Charcot-Marie-Tooth disease. | Bergoffen J | Science (New York, N.Y.) | 1993 | PMID: 8266101 |
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Text-mined citations for rs116840821 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.