ClinVar Genomic variation as it relates to human health
NM_002047.4(GARS1):c.1660G>A (p.Asp554Asn)
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.
Pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002047.4(GARS1):c.1660G>A (p.Asp554Asn)
Variation ID: 9208 Accession: VCV000009208.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p14.3 7: 30626280 (GRCh38) [ NCBI UCSC ] 7: 30665896 (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 Feb 28, 2015 Dec 9, 2023 Jan 1, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002047.4:c.1660G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002038.2:p.Asp554Asn missense NM_001316772.1:c.1498G>A NP_001303701.1:p.Asp500Asn missense NC_000007.14:g.30626280G>A NC_000007.13:g.30665896G>A NG_007942.1:g.36716G>A LRG_243:g.36716G>A LRG_243t1:c.1660G>A P41250:p.Asp554Asn - Protein change
- D500N, D554N
- Other names
- -
- Canonical SPDI
- NC_000007.14:30626279: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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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GARS1 | - | - |
GRCh38 GRCh37 |
767 | 802 |
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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 1, 2019 | RCV000009787.17 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jun 16, 2017 | RCV000009788.13 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000790257.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 16, 2017 | RCV001161100.6 |
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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Uncertain significance
(Jun 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Distal hereditary motor neuronopathy type 5
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001322945.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2D
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001322946.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Distal Spinal Muscular Atrophy
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001322944.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2D
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439953.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease type 2D
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174547.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929657.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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Pathogenic
(Nov 01, 2014)
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no assertion criteria provided
Method: literature only
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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004045986.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment on evidence:
In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 … (more)
In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Del Bo et al. (2006) identified a heterozygous c.2016G-A transition in exon 13 of the GARS gene, resulting in an asp500-to-asn (D500N) substitution. The mutation was not identified in 100 control Italian individuals. There was broad intrafamilial phenotype variability, with some members presenting symptoms in childhood and some in adulthood. Sensory involvement was variable. Functional studies of the variant were not performed. Variant Function Griffin et al. (2014) found that the D500N variant did not impair GARS function in 2 in vitro assays: the variant had normal enzyme activity and showed normal intracellular localization. (less)
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Pathogenic
(Nov 01, 2014)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030008.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 … (more)
In a large Italian multigenerational family in which affected members had either Charcot-Marie-Tooth disease type 2D (CMT2D; 601472) or autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Del Bo et al. (2006) identified a heterozygous c.2016G-A transition in exon 13 of the GARS gene, resulting in an asp500-to-asn (D500N) substitution. The mutation was not identified in 100 control Italian individuals. There was broad intrafamilial phenotype variability, with some members presenting symptoms in childhood and some in adulthood. Sensory involvement was variable. Functional studies of the variant were not performed. Variant Function Griffin et al. (2014) found that the D500N variant did not impair GARS function in 2 in vitro assays: the variant had normal enzyme activity and showed normal intracellular localization. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease type 2D
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001760939.2
First in ClinVar: Jul 24, 2021 Last updated: Oct 01, 2022 |
Comment:
GARS1-HMSN (CMT2D & dSMA-V) [Del Bo et al 2006]
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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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GARS1-Associated Axonal Neuropathy. | Adam MP | - | 2021 | PMID: 20301420 |
Evolutionary and structural annotation of disease-associated mutations in human aminoacyl-tRNA synthetases. | Datt M | BMC genomics | 2014 | PMID: 25476837 |
Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations. | Griffin LB | Human mutation | 2014 | PMID: 25168514 |
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 |
Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation. | Del Bo R | Neurology | 2006 | PMID: 16534118 |
Text-mined citations for rs137852647 ...
HelpRecord last updated May 01, 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.