Variant summary: GNE c.173C>T (p.Pro58Leu) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD v2.1, Exomes dataset). c.173C>T has been reported in the literature in multiple compound heterozygous individuals affected with Inclusion Body Myopathy 2 (e.g., Mori-Yoshimura_2012, Cho_2014, Zhao_2015, Murtazina_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24027297, 22507750, 36360228, 25986339). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.80C>T (p.Pro27Leu)
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.
(6)
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/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005476.7(GNE):c.80C>T (p.Pro27Leu)
Variation ID: 551266 Accession: VCV000551266.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 36249276 (GRCh38) [ NCBI UCSC ] 9: 36249273 (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 Aug 5, 2018 Jun 17, 2024 Dec 2, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005476.7:c.80C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Pro27Leu missense NM_001128227.3:c.173C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Pro58Leu missense NM_001190383.3:c.80C>T NP_001177312.1:p.Pro27Leu missense NM_001190384.3:c.-13-2794C>T intron variant NM_001190388.2:c.-13-2794C>T intron variant NM_001374797.1:c.80C>T NP_001361726.1:p.Pro27Leu missense NM_001374798.1:c.-13-2794C>T intron variant NC_000009.12:g.36249276G>A NC_000009.11:g.36249273G>A NG_008246.1:g.32769C>T LRG_1197:g.32769C>T LRG_1197t1:c.173C>T LRG_1197p1:p.Pro58Leu LRG_1197t2:c.80C>T LRG_1197p2:p.Pro27Leu - Protein change
- P58L, P27L
- Other names
- -
- Canonical SPDI
- NC_000009.12:36249275:G: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
|||
| GNE | - | - |
GRCh38 GRCh37 |
1051 | 1129 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 2, 2023 | RCV000666276.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 5, 2022 | RCV001214257.6 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 29, 2022 | RCV003140061.3 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790539.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
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Pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020797.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: GNE c.173C>T (p.Pro58Leu) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four … (more)
Variant summary: GNE c.173C>T (p.Pro58Leu) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD v2.1, Exomes dataset). c.173C>T has been reported in the literature in multiple compound heterozygous individuals affected with Inclusion Body Myopathy 2 (e.g., Mori-Yoshimura_2012, Cho_2014, Zhao_2015, Murtazina_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24027297, 22507750, 36360228, 25986339). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Likely pathogenic
(Jun 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003828625.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Oct 05, 2022)
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001385931.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro58 amino acid residue in GNE. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro58 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21708040, 27829678, 28717665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 551266). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 22507750, 24005727, 24027297). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the GNE protein (p.Pro58Leu). (less)
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Pathogenic
(Dec 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
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GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004191643.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Apr 20, 2021)
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no assertion criteria provided
Method: clinical testing
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Nonaka myopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002075665.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro58 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21708040, 27829678, 28717665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 551266). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 22507750, 24005727, 24027297). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the GNE protein (p.Pro58Leu).
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:
Variant summary: GNE c.173C>T (p.Pro58Leu) results in a non-conservative amino acid change located in the UDP-N-acetylglucosamine 2-epimerase domain (IPR003331) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes (gnomAD v2.1, Exomes dataset). c.173C>T has been reported in the literature in multiple compound heterozygous individuals affected with Inclusion Body Myopathy 2 (e.g., Mori-Yoshimura_2012, Cho_2014, Zhao_2015, Murtazina_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24027297, 22507750, 36360228, 25986339). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro58 amino acid residue in GNE. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21708040, 27829678, 28717665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 551266). This missense change has been observed in individuals with autosomal recessive GNE-related myopathy (PMID: 22507750, 24005727, 24027297). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 58 of the GNE protein (p.Pro58Leu).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic and Clinical Spectrum of GNE Myopathy in Russia. | Murtazina A | Genes | 2022 | PMID: 36360228 |
| Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. | Garland J | Molecular genetics & genomic medicine | 2017 | PMID: 28717665 |
| Missing genetic variations in GNE myopathy: rearrangement hotspots encompassing 5'UTR and founder allele. | Zhu W | Journal of human genetics | 2017 | PMID: 27829678 |
| Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy. | Cerino M | Journal of neuromuscular diseases | 2015 | PMID: 27858732 |
| Mutational spectrum and clinical features in 35 unrelated mainland Chinese patients with GNE myopathy. | Zhao J | Journal of the neurological sciences | 2015 | PMID: 25986339 |
| 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 |
| GNE myopathy in India. | Nalini A | Neurology India | 2013 | PMID: 24005727 |
| Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. | Mori-Yoshimura M | Journal of the neurological sciences | 2012 | PMID: 22507750 |
| Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE. | Boyden SE | BMC medical genetics | 2011 | PMID: 21708040 |
Text-mined citations for rs1236647498 ...
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 Sep 29, 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.