VCV000217169.15 - ClinVar

NM_000166.6(GJB1):c.44G>A (p.Arg15Gln)

Germline

Classification

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.

(6)

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

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.44G>A (p.Arg15Gln)

Variation ID: 217169 Accession: VCV000217169.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71223751 (GRCh38) [ NCBI UCSC ] X: 70443601 (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	Oct 19, 2015	May 1, 2024	Dec 9, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000166.6:c.44G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000157.1:p.Arg15Gln	missense
NM_001097642.3:c.44G>A	NP_001091111.1:p.Arg15Gln	missense
NC_000023.11:g.71223751G>A
NC_000023.10:g.70443601G>A
NG_008357.1:g.13540G>A
LRG_245:g.13540G>A
LRG_245t2:c.44G>A	LRG_245p2:p.Arg15Gln
	P08034:p.Arg15Gln

... more HGVS ... less HGVS

Protein change

R15Q

Other names

Canonical SPDI

NC_000023.11:71223750:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA279084 UniProtKB: P08034#VAR_002015 dbSNP: rs863224974 VarSome

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
Gene	OMIM	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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 21, 2022	RCV000235929.13
Charcot-Marie-Tooth Neuropathy X	Pathogenic (1)	criteria provided, single submitter	Dec 9, 2023	RCV000234336.16
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Nov 9, 2020	RCV002327051.9
Charcot-Marie-Tooth disease X-linked dominant 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 27, 2023	RCV003447516.2

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.
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000255689.3 First in ClinVar: Oct 19, 2015 Last updated: Dec 31, 2022	Publications: PubMed (16) PubMed: 8162049‚ 10093067‚ 10586261‚ 11325342‚ 15006706‚ 9364054‚ 17353473‚ 22464564‚ 18379723‚ 15719046‚ 14706470‚ 28286897‚ 32010055‚ 32376792‚ 27098783‚ 28768847 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 21, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000293139.11 First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Dec 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth Neuropathy X Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283687.8 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Publications: PubMed (16) PubMed: 8162049‚ 10586261‚ 11718056‚ 14706470‚ 15719046‚ 17353473‚ 18379723‚ 19062535‚ 22464564‚ 9364054‚ 11325342‚ 15006706‚ 9328258‚ 10093067‚ 10639608‚ 24078732 Comment: 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). … (more) 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. (less)
Pathogenic (May 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease X-linked dominant 1 (X-linked dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175227.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (6) PubMed: 8162049‚ 9364054‚ 11325342‚ 15006706‚ 28286897‚ 32010055 Comment: 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 … (more) 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). (less)
Pathogenic (Jul 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease X-linked dominant 1 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004704510.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Publications: PubMed (1) PubMed: 37284795 Comment: ACMG criteria used to clasify this variant: PS3, PP3_STR, PM1, PM2_SUP Clinical Features: Peripheral axonal neuropathy (present)
Pathogenic (Nov 09, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002639693.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 10521546‚ 11325342‚ 14706470‚ 15006706‚ 27098783‚ 32010055‚ 8162049‚ 9328258‚ 9364054 Comment: 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 … (more) 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. (less)

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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).

Comment:

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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.	Record CJ	Brain : a journal of neurology	2023	PMID: 37284795
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.	Volodarsky M	Journal of medical genetics	2021	PMID: 32376792
GJB1 Mutation-A Disease Spectrum: Report of Case Series.	Niu J	Frontiers in neurology	2020	PMID: 32010055
Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).	Panosyan FB	Neurology	2017	PMID: 28768847
Charcot-Marie-Tooth disease: genetic subtypes in the Sardinian population.	Lorefice L	Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology	2017	PMID: 28286897
Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients.	Sun B	Chinese medical journal	2016	PMID: 27098783
Charcot-Marie-Tooth disease: genetic and clinical spectrum in a Spanish clinical series.	Sivera R	Neurology	2013	PMID: 24078732
Hand weakness in Charcot-Marie-Tooth disease 1X.	Arthur-Farraj PJ	Neuromuscular disorders : NMD	2012	PMID: 22464564
[Spectrum and frequency of mutations in the connexin 32 gene (GJB1) in hereditary and sensory neuropathy type 1X patients from Bashkortostan].	Khidiianova IM	Genetika	2008	PMID: 19062535
Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease.	Mandich P	Journal of human genetics	2008	PMID: 18379723
CMT1X phenotypes represent loss of GJB1 gene function.	Shy ME	Neurology	2007	PMID: 17353473
Mutation screening of Cx32 in Han Chinese patients with Charcot-Marie-Tooth disease.	Zhang RX	Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences	2005	PMID: 15719046
Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease.	Wang HL	Neurobiology of disease	2004	PMID: 15006706
Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation.	Capasso M	Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology	2004	PMID: 14706470
[X-linked recessive Charcot-Marie-Tooth disease and Cx32 gene mutation].	Luo W	Zhonghua nei ke za zhi	2001	PMID: 11718056
Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease.	Abrams CK	Brain research	2001	PMID: 11325342
Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease.	Gutierrez A	Muscle & nerve	2000	PMID: 10639608
Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.	Hahn AF	Annals of the New York Academy of Sciences	1999	PMID: 10586261
X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).	Senderek J	Journal of the neurological sciences	1999	PMID: 10521546
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
Missense mutation (R15W) of the connexin32 gene in a family with X chromosomal Charcot-Marie-Tooth neuropathy with only female family members affected.	Wicklein EM	Journal of neurology, neurosurgery, and psychiatry	1997	PMID: 9328258
Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).	Fairweather N	Human molecular genetics	1994	PMID: 8162049
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Text-mined citations for rs863224974 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000166.6(GJB1):c.44G>A (p.Arg15Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs863224974 ...