ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.527A>T (p.Asp176Val)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005476.7(GNE):c.527A>T (p.Asp176Val)
Variation ID: 41233 Accession: VCV000041233.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 36246120 (GRCh38) [ NCBI UCSC ] 9: 36246117 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 3, 2013 Feb 28, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005476.7:c.527A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Asp176Val missense NM_001128227.3:c.620A>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Asp207Val missense NM_001190383.3:c.527A>T NP_001177312.1:p.Asp176Val missense NM_001190384.3:c.350A>T NP_001177313.1:p.Asp117Val missense NM_001190388.2:c.350A>T NP_001177317.2:p.Asp117Val missense NM_001374797.1:c.527A>T NP_001361726.1:p.Asp176Val missense NM_001374798.1:c.350A>T NP_001361727.1:p.Asp117Val missense NC_000009.12:g.36246120T>A NC_000009.11:g.36246117T>A NG_008246.1:g.35925A>T LRG_1197:g.35925A>T LRG_1197t1:c.620A>T LRG_1197p1:p.Asp207Val LRG_1197t2:c.527A>T LRG_1197p2:p.Asp176Val Q9Y223:p.Asp176Val - Protein change
- D207V, D176V, D117V
- Other names
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- Canonical SPDI
- NC_000009.12:36246119:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
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HI score
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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. |
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GNE | - | - |
GRCh38 GRCh37 |
1033 | 1108 |
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. |
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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV000343796.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000726858.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001060883.6 |
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
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000480110.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The GNE c.527A>T (p.Asp176Val) variant is a well-described pathogenic variant (Mori-Yoshimura et al. 2014; Zhao et al. 2015). In the Japanese nationwide patient registry, which … (more)
The GNE c.527A>T (p.Asp176Val) variant is a well-described pathogenic variant (Mori-Yoshimura et al. 2014; Zhao et al. 2015). In the Japanese nationwide patient registry, which includes 121 patients with GNE-related myopathy, the p.Asp176Val variant is found in a homozygous state in one individual, in a compound heterozygous state with the common p.Val572Leu variant in 24 individuals, in a compound heterozygous state with different variants in 29 individuals, and in a heterozygous state in three individuals (Mori-Yoshimura et al. 2014). The p.Asp176Val variant is additionally reported in three other studies in which it is found in 37 patients of Chinese origin including three in a homozygous state and 34 in a compound heterozygous state, and in one Korean patient in a compound heterozygous state (Lu et al; 2011; Choi et al. 2015; Zhao et al. 2015). The p.Asp176Val variant was detected in a heterozygous state in one of 520 control individuals and is reported at a frequency of 0.00046 in the East Asian population of the Exome Aggregation Consortium. Functional studies using a p.Asp176Val transgenic mouse model found that the mouse mimicked the clinical, histopathological, and biochemical features of GNE-related myopathy, however, the p.Asp176Val variant was also reported in a homozygous state in a 71 year old asymptomatic individual (Cho et al. 2014). Although the p.Asp176Val variant has been identified at a high frequency of individuals with GNE-related myopathy, the variability in clinical presentation is suggestive of a milder phenotype and potentially reduced penetrance. Based on the collective evidence, the p.Asp176Val variant is classified as pathogenic for GNE-related myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193885.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_001128227.2(GNE):c.620A>T(D207V, aka D176V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 17704511, 14707127 and 24027297. … (more)
NM_001128227.2(GNE):c.620A>T(D207V, aka D176V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 17704511, 14707127 and 24027297. Classification of NM_001128227.2(GNE):c.620A>T(D207V, aka D176V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004199377.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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GNE myopathy
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267347.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Pathogenic
(Nov 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000703656.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015173.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: GNE c.620A>T (p.Asp207Val) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three … (more)
Variant summary: GNE c.620A>T (p.Asp207Val) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251312 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (5.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.620A>T has been widely reported in the literature in multiple individuals affected with features of Inclusion Body Myopathy 2 (example,Nishino_2002, Noguchi_2004, Ishihara_2008, Choi_2015, Chanana_2017, Miao_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Nishino_2002). The most pronounced variant effect results in <10% of normal UDP-N acetylglucosamine 2-epimerase enzyme activity in leukocytes from homozygous as well as compound heterozygous patients with Distal myopathy with rimmed vacuoles (DMRV). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sialuria
GNE myopathy
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810421.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236039.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Sialuria
GNE myopathy
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001225600.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 207 of the GNE protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 207 of the GNE protein (p.Asp207Val). This variant is present in population databases (rs139425890, gnomAD 0.06%). This missense change has been observed in individuals with distal myopathy (PMID: 12473753, 14707127, 18383535, 26161358, 28403181, 29307446). ClinVar contains an entry for this variant (Variation ID: 41233). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. Experimental studies have shown that this missense change affects GNE function (PMID: 14707127, 20030229, 24474513, 28895049). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Nonaka myopathy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458442.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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GNE myopathy
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000058063.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A case report: identification of a novel exon 1 deletion mutation in the GNE gene in a Chinese patient with GNE myopathy. | Miao J | Medicine | 2020 | PMID: 33031330 |
GNE Myopathy. | Adam MP | - | 2020 | PMID: 20301439 |
GNE myopathy in Chinese population: hotspot and novel mutations. | Chen Y | Journal of human genetics | 2019 | PMID: 30390020 |
Mutation Spectrum of GNE Myopathy in the Indian Sub-Continent. | Bhattacharya S | Journal of neuromuscular diseases | 2018 | PMID: 29480215 |
GNE myopathy caused by a synonymous mutation leading to aberrant mRNA splicing. | Zhu W | Neuromuscular disorders : NMD | 2018 | PMID: 29307446 |
Mutation in GNE Downregulates Peroxiredoxin IV Altering ER Redox Homeostasis. | Chanana P | Neuromolecular medicine | 2017 | PMID: 28895049 |
Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing. | Yu M | PloS one | 2017 | PMID: 28403181 |
Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy. | Cerino M | Journal of neuromuscular diseases | 2015 | PMID: 27858732 |
Novel Mutation of the GNE Gene Presenting Atypical Mild Clinical Feature: A Korean Case Report. | Choi YA | Annals of rehabilitation medicine | 2015 | PMID: 26161358 |
Mutational spectrum and clinical features in 35 unrelated mainland Chinese patients with GNE myopathy. | Zhao J | Journal of the neurological sciences | 2015 | PMID: 25986339 |
Nationwide patient registry for GNE myopathy in Japan. | Mori-Yoshimura M | Orphanet journal of rare diseases | 2014 | PMID: 25303967 |
Mutation update for GNE gene variants associated with GNE myopathy. | Celeste FV | Human mutation | 2014 | PMID: 24796702 |
Two recurrent mutations are associated with GNE myopathy in the North of Britain. | Chaouch A | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24695763 |
Role of UDP-N-acetylglucosamine2-epimerase/N-acetylmannosamine kinase (GNE) in β1-integrin-mediated cell adhesion. | Grover S | Molecular neurobiology | 2014 | PMID: 24474513 |
Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy). | Cho A | Journal of neurology, neurosurgery, and psychiatry | 2014 | PMID: 24027297 |
Distal myopathy with rimmed vacuoles: clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients. | Lu X | Neurological research | 2011 | PMID: 22196754 |
Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria. | Kurochkina N | Glycobiology | 2010 | PMID: 19917666 |
[Development of therapy for distal myopathy with rimmed vacuoles]. | Nishino I | Rinsho shinkeigaku = Clinical neurology | 2009 | PMID: 20030229 |
Atypical Parkinsonism in distal myopathy with rimmed vacuoles. | Ishihara T | Movement disorders : official journal of the Movement Disorder Society | 2008 | PMID: 18383535 |
A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. | Malicdan MC | Human molecular genetics | 2007 | PMID: 17704511 |
Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy. | Broccolini A | Human mutation | 2004 | PMID: 15146476 |
Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. | Tomimitsu H | Neurology | 2004 | PMID: 15136692 |
Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. | Noguchi S | The Journal of biological chemistry | 2004 | PMID: 14707127 |
Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. | Nishino I | Neurology | 2002 | PMID: 12473753 |
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. | Eisenberg I | Nature genetics | 2001 | PMID: 11528398 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNE | - | - | - | - |
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Text-mined citations for rs139425890 ...
HelpRecord last updated Mar 17, 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.