Published functional studies demonstrate impaired enzyme activity, dimer instability, and inappropriate ligand binding (PMID: 17595294, 21737751, 26503042); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10732809, 21737751, 25168514, 25476837, 17595294, 17035524, 8872480, 26503042, 27008886, 29520015, 12690580)
ClinVar Genomic variation as it relates to human health
NM_002047.4(GARS1):c.880G>C (p.Gly294Arg)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002047.4(GARS1):c.880G>C (p.Gly294Arg)
Variation ID: 9204 Accession: VCV000009204.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p14.3 7: 30609729 (GRCh38) [ NCBI UCSC ] 7: 30649345 (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 Feb 28, 2015 Sep 16, 2024 Dec 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002047.4:c.880G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002038.2:p.Gly294Arg missense NM_001316772.1:c.718G>C NP_001303701.1:p.Gly240Arg missense NC_000007.14:g.30609729G>C NC_000007.13:g.30649345G>C NG_007942.1:g.20165G>C LRG_243:g.20165G>C LRG_243t1:c.880G>C P41250:p.Gly294Arg - Protein change
- G240R, G294R
- Other names
- -
- Canonical SPDI
- NC_000007.14:30609728:G:C
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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. |
|||
| GARS1 | - | - |
GRCh38 GRCh37 |
781 | 817 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
no assertion criteria provided
|
Jan 6, 2016 | RCV000009782.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 18, 2023 | RCV000327196.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 17, 2023 | RCV000692132.8 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000789142.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 20, 2023 | RCV004018608.1 |
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
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329356.7
First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate impaired enzyme activity, dimer instability, and inappropriate ligand binding (PMID: 17595294, 21737751, 26503042); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate impaired enzyme activity, dimer instability, and inappropriate ligand binding (PMID: 17595294, 21737751, 26503042); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10732809, 21737751, 25168514, 25476837, 17595294, 17035524, 8872480, 26503042, 27008886, 29520015, 12690580) (less)
|
|
|
Pathogenic
(Aug 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000819941.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the GARS protein (p.Gly294Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the GARS protein (p.Gly294Arg). This variant is present in population databases (rs137852643, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8872480, 10732809, 12690580; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GARS function (PMID: 17035524, 17595294, 21737751, 26138142, 26503042, 27008886). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004873230.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.880G>C (p.G294R) alteration is located in exon 7 (coding exon 7) of the GARS gene. This alteration results from a G to C substitution … (more)
The c.880G>C (p.G294R) alteration is located in exon 7 (coding exon 7) of the GARS gene. This alteration results from a G to C substitution at nucleotide position 880, causing the glycine (G) at amino acid position 294 to be replaced by an arginine (R)._x000D_ _x000D_ for autosomal dominant GARS1-related axonal neuropathy; however, its clinical significance for autosomal recessive Cytoplasmic and mitochondrial glycyl-tRNA synthetase deficiency is uncertain. Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249268) total alleles studied. The highest observed frequency was 0.001% (1/113114) of European (non-Finnish) alleles. This alteration has been detected in the heterozygous state in multiple individuals with clinical features of GARS1-related axonal neuropathy (Antonellis, 2003; External communication). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, G294R is deleterious and is highly destabilizing to the local structure (Ambry internal data). In multiple assays testing GARS function, this variant showed functionally abnormal results (Antonellis, 2006; Nangle, 2007; He, 2011; He, 2015; Niehues, 2015; Malissovas, 2016; Mo, 2018; Cui, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(May 01, 2003)
|
no assertion criteria provided
Method: literature only
|
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030003.5
First in ClinVar: Apr 04, 2013 Last updated: Oct 28, 2023 |
Comment on evidence:
In 2 families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) first reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997), Antonellis et al. … (more)
In 2 families with Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) first reported by Ionasescu et al. (1996) and Pericak-Vance et al. (1997), Antonellis et al. (2003) identified a heterozygous c.1236G-C change in the GARS gene, resulting in a gly240-to-arg (G240R) substitution. The mutation was absent in 368 unrelated chromosomes. (less)
|
|
|
Uncertain significance
(Jan 06, 2016)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease type 2D
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174557.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000928494.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Charcot-Marie-Tooth disease type 2D
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001760932.2
First in ClinVar: Jul 24, 2021 Last updated: Oct 01, 2022 |
Comment:
GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016]
|
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the GARS protein (p.Gly294Arg). This variant is present in population databases (rs137852643, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8872480, 10732809, 12690580; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GARS function (PMID: 17035524, 17595294, 21737751, 26138142, 26503042, 27008886). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.880G>C (p.G294R) alteration is located in exon 7 (coding exon 7) of the GARS gene. This alteration results from a G to C substitution at nucleotide position 880, causing the glycine (G) at amino acid position 294 to be replaced by an arginine (R)._x000D_ _x000D_ for autosomal dominant GARS1-related axonal neuropathy; however, its clinical significance for autosomal recessive Cytoplasmic and mitochondrial glycyl-tRNA synthetase deficiency is uncertain. Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249268) total alleles studied. The highest observed frequency was 0.001% (1/113114) of European (non-Finnish) alleles. This alteration has been detected in the heterozygous state in multiple individuals with clinical features of GARS1-related axonal neuropathy (Antonellis, 2003; External communication). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, G294R is deleterious and is highly destabilizing to the local structure (Ambry internal data). In multiple assays testing GARS function, this variant showed functionally abnormal results (Antonellis, 2006; Nangle, 2007; He, 2011; He, 2015; Niehues, 2015; Malissovas, 2016; Mo, 2018; Cui, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016]
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:
Published functional studies demonstrate impaired enzyme activity, dimer instability, and inappropriate ligand binding (PMID: 17595294, 21737751, 26503042); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10732809, 21737751, 25168514, 25476837, 17595294, 17035524, 8872480, 26503042, 27008886, 29520015, 12690580)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the GARS protein (p.Gly294Arg). This variant is present in population databases (rs137852643, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8872480, 10732809, 12690580; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GARS function (PMID: 17035524, 17595294, 21737751, 26138142, 26503042, 27008886). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.880G>C (p.G294R) alteration is located in exon 7 (coding exon 7) of the GARS gene. This alteration results from a G to C substitution at nucleotide position 880, causing the glycine (G) at amino acid position 294 to be replaced by an arginine (R)._x000D_ _x000D_ for autosomal dominant GARS1-related axonal neuropathy; however, its clinical significance for autosomal recessive Cytoplasmic and mitochondrial glycyl-tRNA synthetase deficiency is uncertain. Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249268) total alleles studied. The highest observed frequency was 0.001% (1/113114) of European (non-Finnish) alleles. This alteration has been detected in the heterozygous state in multiple individuals with clinical features of GARS1-related axonal neuropathy (Antonellis, 2003; External communication). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, G294R is deleterious and is highly destabilizing to the local structure (Ambry internal data). In multiple assays testing GARS function, this variant showed functionally abnormal results (Antonellis, 2006; Nangle, 2007; He, 2011; He, 2015; Niehues, 2015; Malissovas, 2016; Mo, 2018; Cui, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016]
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules. | Cui Q | Cell | 2023 | PMID: 36738734 |
| GARS1-Associated Axonal Neuropathy. | Adam MP | - | 2021 | PMID: 20301420 |
| Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. | Mo Z | Nature communications | 2018 | PMID: 29520015 |
| Dimerization is required for GARS-mediated neurotoxicity in dominant CMT disease. | Malissovas N | Human molecular genetics | 2016 | PMID: 27008886 |
| CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. | He W | Nature | 2015 | PMID: 26503042 |
| Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases. | Niehues S | Nature communications | 2015 | PMID: 26138142 |
| Dispersed disease-causing neomorphic mutations on a single protein promote the same localized conformational opening. | He W | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21737751 |
| Charcot-Marie-Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. | Nangle LA | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17595294 |
| Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. | Antonellis A | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2006 | PMID: 17035524 |
| Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. | Antonellis A | American journal of human genetics | 2003 | PMID: 12690580 |
| Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity. | Pericak-Vance MA | Neurogenetics | 1997 | PMID: 10732809 |
| Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). | Ionasescu V | Human molecular genetics | 1996 | PMID: 8872480 |
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Text-mined citations for rs137852643 ...
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.