The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy.
ClinVar Genomic variation as it relates to human health
NM_005476.7(GNE):c.1892C>T (p.Ala631Val)
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.
(21)
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
21
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.1892C>T (p.Ala631Val)
Variation ID: 6035 Accession: VCV000006035.62
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.3 9: 36218224 (GRCh38) [ NCBI UCSC ] 9: 36218221 (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 9, 2016 Oct 20, 2024 Jun 21, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005476.7:c.1892C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005467.1:p.Ala631Val missense NM_001128227.3:c.1985C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121699.1:p.Ala662Val missense NM_001190383.3:c.1670C>T NP_001177312.1:p.Ala557Val missense NM_001190384.3:c.1562C>T NP_001177313.1:p.Ala521Val missense NM_001190388.2:c.1715C>T NP_001177317.2:p.Ala572Val missense NM_001374797.1:c.1739C>T NP_001361726.1:p.Ala580Val missense NM_001374798.1:c.1715C>T NP_001361727.1:p.Ala572Val missense NC_000009.12:g.36218224G>A NC_000009.11:g.36218221G>A NG_008246.1:g.63821C>T LRG_1197:g.63821C>T LRG_1197t1:c.1985C>T LRG_1197p1:p.Ala662Val LRG_1197t2:c.1892C>T LRG_1197p2:p.Ala631Val - Protein change
- A631V, A662V, A521V, A557V, A572V, A580V
- Other names
- -
- Canonical SPDI
- NC_000009.12:36218223: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.
-
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00014
- 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 |
1050 | 1128 | |
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 (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2024 | RCV000006406.23 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 21, 2024 | RCV000254883.36 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000763617.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 12, 2024 | RCV004525844.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV004566685.1 |
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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538036.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain … (more)
The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy. (less)
|
|
|
Pathogenic
(Apr 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331895.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 13
Sex: mixed
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Sialuria
GNE myopathy GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894471.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194129.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, … (more)
NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) 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)
|
|
|
Pathogenic
(Dec 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: no
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059317.1
First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022 |
|
|
|
Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024869.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV000638331.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613535.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
GNE myopathy Sialuria
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163611.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
GNE myopathy
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251481.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; … (more)
The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577401.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
|
|
|
Pathogenic
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226607.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2, PM3_strong, PS3, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005039440.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Thrombocytopenia 12 with or without myopathy
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051801.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
GNE myopathy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001527752.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 12, 2024)
|
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: SCV005062084.2
First in ClinVar: Jun 29, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in the encoded protein sequence. Five of … (more)
Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321742.10
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this … (more)
Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127) (less)
|
|
|
Pathogenic
(Aug 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248054.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Dec 10, 2002)
|
no assertion criteria provided
Method: literature only
|
NONAKA MYOPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026589.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In 1 of 9 unrelated Japanese patients with Nonaka myopathy (NM; 605820), Tomimitsu et al. (2002) identified a homozygous 1943C-T transition in exon 11 of … (more)
In 1 of 9 unrelated Japanese patients with Nonaka myopathy (NM; 605820), Tomimitsu et al. (2002) identified a homozygous 1943C-T transition in exon 11 of the GNE gene, resulting in an ala631-to-val (A631V) substitution. Of the 9 patients, this patient had the latest age of onset, the slowest progression of disease, and was still able to stand 30 years after onset. In affected members of an American family with NM, Vasconcelos et al. (2002) identified compound heterozygous mutations in the GNE gene: A631V and a 698T-C transition in exon 4 resulting in a val216-to-ala (V216A; 603824.0017) substitution. Vasconcelos et al. (2002) called the disorder quadriceps-sparing inclusion body myopathy. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Nonaka myopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458429.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
GNE myopathy
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001364094.2
First in ClinVar: Jun 22, 2020 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) 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.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763).
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
Comment:
PP3, PM2, PM3_strong, PS3, PS4
Comment:
Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127)
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:
The c.1985C>T (p.Ala662Val) is a missense variant in the GNE gene where missense pathogenic variants have been reported. It is located in the kinase domain of the protein, and functional studies have shown that the kinase activity is dramatically reduced in cells carrying this variant (Nogushi et al. 2004). It is absent or not frequent in the control population databases (0% in 1000 genomes and Exome Sequencing Project, and 0.013% in ExAc), and in silico computational algorithms predicted this variant to be deleterious to protein function and exhibits a high CADD score (27.1). Finally, this variant has been described as pathogenic by ClinVar and the Emory Genetics Laboratory. Therefore, this collective evidence supports the classification of the c.1985C>T (p.Ala662Val) as a recessive pathogenic variant for inclusion body myopathy.
Comment:
NM_001128227.2(GNE):c.1985C>T(A662V) is classified as pathogenic in the context of GNE myopathy. Sources cited for classification include the following: PMID 22343627, 15987957, 14707127, 12473769, 12177386, 12497639, 24695763 and 16503651. Classification of NM_001128227.2(GNE):c.1985C>T(A662V) 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.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 662 of the GNE protein (p.Ala662Val). This variant is present in population databases (rs62541771, gnomAD 0.02%). This missense change has been observed in individuals with GNE myopathy (PMID: 24796702). It is commonly reported in individuals of British and Chinese ancestry (PMID: 22196754, 24695763). This variant is also known as p.Ala631Val. ClinVar contains an entry for this variant (Variation ID: 6035). 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, 15987957, 16503651). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1985C>T (p.A662V) variant has been observed in the homozygous or compound heterozygous state in individuals with GNE myopathy (PMID: 12177386; 12473769; 12497639; 15136692; 19596068; 21131200; 22196754; 22883483; 24695763).
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
Comment:
PP3, PM2, PM3_strong, PS3, PS4
Comment:
Variant summary: GNE c.1985C>T (p.Ala662Val), also referred to as c.1892C>T (p.Ala631Val), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251482 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GNE causing Inclusion Body Myopathy 2 (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.1985C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Inclusion Body Myopathy 2 (e.g. Chaouch_2014). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (eg. Noguchi_2004, Sparks_2005). The most pronounced variant effect results in 10%-<30% of normal UDP-GlcNAc 2-epimerase and ManNAc kinase activities. The following publications have been ascertained in the context of this evaluation (PMID: 14707127, 15987957, 24695763). ClinVar contains an entry for this variant (Variation ID: 6035). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34676965, 19917666, 15987957, 22507750, 12177386, 16503651, 31127727, 35138478, 26968811, 24796702, 38674419, 37510394, 24695763, 14707127)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical, genetic, and pathological characterization of GNE myopathy in China. | Lv XQ | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2022 | PMID: 35138478 |
| Mutation Spectrum of GNE Myopathy in the Indian Sub-Continent. | Bhattacharya S | Journal of neuromuscular diseases | 2018 | PMID: 29480215 |
| Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy. | Bosch-Morató M | Oncotarget | 2016 | PMID: 26968811 |
| Nationwide patient registry for GNE myopathy in Japan. | Mori-Yoshimura M | Orphanet journal of rare diseases | 2014 | PMID: 25303967 |
| Sialylation of Thomsen-Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy. | Leoyklang P | Biomarkers in medicine | 2014 | PMID: 25123033 |
| 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 |
| Limb-girdle phenotype is frequent in patients with myopathy associated with GNE mutations. | Park YE | Journal of the neurological sciences | 2012 | PMID: 22883483 |
| 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 |
| Crystal structures of N-acetylmannosamine kinase provide insights into enzyme activity and inhibition. | Martinez J | The Journal of biological chemistry | 2012 | PMID: 22343627 |
| 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 |
| Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex. | Nemunaitis G | Human gene therapy | 2011 | PMID: 21517694 |
| Clinical and molecular genetic analysis in Chinese patients with distal myopathy with rimmed vacuoles. | Li H | Journal of human genetics | 2011 | PMID: 21307865 |
| Novel GNE mutations in two phenotypically distinct HIBM2 patients. | Weihl CC | Neuromuscular disorders : NMD | 2011 | PMID: 21131200 |
| Novel GNE mutations in hereditary inclusion body myopathy patients of non-Middle Eastern descent. | Saechao C | Genetic testing and molecular biomarkers | 2010 | PMID: 20059379 |
| Crystal structure of the N-acetylmannosamine kinase domain of GNE. | Tong Y | PloS one | 2009 | PMID: 19841673 |
| Hereditary inclusion body myopathy: a decade of progress. | Huizing M | Biochimica et biophysica acta | 2009 | PMID: 19596068 |
| Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study. | Sparks S | BMC neurology | 2007 | PMID: 17261181 |
| Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy. | Penner J | Biochemistry | 2006 | PMID: 16503651 |
| Single nucleotide polymorphisms in the dystroglycan gene do not correlate with disease severity in hereditary inclusion body myopathy. | Gottlieb E | Molecular genetics and metabolism | 2005 | PMID: 16112887 |
| Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human hereditary inclusion body myopathy. | Sparks SE | Glycobiology | 2005 | PMID: 15987957 |
| Distal myopathy with rimmed vacuoles: impaired O-glycan formation in muscular glycoproteins. | Tajima Y | The American journal of pathology | 2005 | PMID: 15793292 |
| Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. | Tomimitsu H | Neurology | 2004 | PMID: 15136692 |
| Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. | Huizing M | Molecular genetics and metabolism | 2004 | PMID: 14972325 |
| 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 |
| Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. | Eisenberg I | Human mutation | 2003 | PMID: 12497639 |
| GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. | Vasconcelos OM | Neurology | 2002 | PMID: 12473769 |
| Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. | Nishino I | Neurology | 2002 | PMID: 12473753 |
| Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. | Tomimitsu H | Neurology | 2002 | PMID: 12177386 |
| 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 rs62541771 ...
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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.