ClinVar Genomic variation as it relates to human health
NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)
Variation ID: 162080 Accession: VCV000162080.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q34 5: 168486503 (GRCh38) [ NCBI UCSC ] 5: 167913508 (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 29, 2016 Feb 14, 2024 May 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002887.4:c.5A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002878.2:p.Asp2Gly missense NC_000005.10:g.168486503A>G NC_000005.9:g.167913508A>G NG_041809.1:g.5046A>G P54136:p.Asp2Gly - Protein change
- D2G
- Other names
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- Canonical SPDI
- NC_000005.10:168486502:A:G
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00013
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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RARS1 | - | - |
GRCh38 GRCh37 |
346 | 369 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Nov 15, 2018 | RCV000149498.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 8, 2023 | RCV002228537.3 |
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
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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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 15, 2018)
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criteria provided, single submitter
Method: research
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Hypomyelinating leukodystrophy 9
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001132579.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Comment:
The homozygous p.Asp2Gly variant in RARS was identified by our study in one individual with Hypomyelinating Leukodystrophy. This variant has been identified in the literature … (more)
The homozygous p.Asp2Gly variant in RARS was identified by our study in one individual with Hypomyelinating Leukodystrophy. This variant has been identified in the literature in the case of two affected homozygous siblings, one girl and one boy. It has also been identified in the case of three compound heterozygous affected probands, two sisters with the variants 45+1G>T, and one unrelated proband with the variant p.Cys32TrpfsTer39. Functional studies have shown that this variant causes severely reduced function of the protein complex (Nafisinia et al. 2017, PMID: 28905880; Wolf et al. 2014, PMID: 24777941). This variant has been identified in <0.01% (6/190228) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs672601372). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Hypomyelinating Leukodystrophy in an autosomal recessive manner based on in vitro functional studies and multiple reports of individuals with this variant and Hypomyelinating Leukodrystrophy in the literature. (less)
Clinical Features:
Abnormality of brain morphology (present)
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002507989.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function … (more)
For these reasons, this variant has been classified as Pathogenic. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 162080). This missense change has been observed in individual(s) with leukodystrophy (PMID: 24777941, 28905880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs672601372, gnomAD 0.008%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2 of the RARS protein (p.Asp2Gly). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hypomyelinating leukodystrophy 9
Affected status: yes
Allele origin:
germline
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Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Accession: SCV000298033.2
First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016 |
Family history: yes
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Pathogenic
(Apr 29, 2014)
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no assertion criteria provided
Method: literature only
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LEUKODYSTROPHY, HYPOMYELINATING, 9
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000196138.3
First in ClinVar: Dec 21, 2014 Last updated: Nov 08, 2019 |
Comment on evidence:
In 2 sisters from the Netherlands with hypomyelinating leukodystrophy-9 (HLD9; 616140), Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene: a c.5A-G … (more)
In 2 sisters from the Netherlands with hypomyelinating leukodystrophy-9 (HLD9; 616140), Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene: a c.5A-G transition (c.5A-G, NM_002887.3) in exon 1, resulting in an asp2-to-gly (D2G) substitution, and a G-to-T transversion in the donor splice site of exon 1 (c.45+1G-T; 107820.0002), predicted to result in the loss of a canonical splice site. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Variant Server databases. The D2G substitution is located in a 72-amino acid domain essential for integration of RARS into the multi-tRNA synthetase complex. Another child from the Netherlands with a similar phenotype was compound heterozygous for D2G and a 2-bp deletion (c.96_97del) in exon 2, resulting in a frameshift and premature termination (Cys32TrpfsTer39; 107820.0003). In a sister and brother, born to unrelated Maltese parents, with HLD9, Nafisinia et al. (2017) identified homozygosity for the D2G mutation in the RARS gene. Fibroblast extracts from one of the sibs showed that levels of RARS protein and the multi-RNA synthetase complex into which it assembles were significantly reduced. (less)
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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
HelpText-mined citations for rs672601372 ...
HelpRecord last updated Mar 30, 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.