ClinVar Genomic variation as it relates to human health
NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)
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); Likely pathogenic(7); Uncertain significance(1); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)
Variation ID: 265854 Accession: VCV000265854.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q34 5: 168510601 (GRCh38) [ NCBI UCSC ] 5: 167937606 (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 Oct 15, 2016 May 12, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002887.4:c.1367C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002878.2:p.Ser456Leu missense NC_000005.10:g.168510601C>T NC_000005.9:g.167937606C>T NG_041809.1:g.29144C>T - Protein change
- S456L
- Other names
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- Canonical SPDI
- NC_000005.10:168510600:C:T
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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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00032
The Genome Aggregation Database (gnomAD), exomes 0.00038
The Genome Aggregation Database (gnomAD) 0.00044
Exome Aggregation Consortium (ExAC) 0.00049
1000 Genomes Project 0.00060
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
1000 Genomes Project 30x 0.00078
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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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
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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Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV000256219.14 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 2, 2024 | RCV001532053.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 10, 2020 | RCV004021037.1 |
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. |
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Likely pathogenic
(Mar 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369637.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_MOD,PS4_MOD,PM3,PP3.
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010047.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747435.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318718.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265854, PMID:28905880). … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265854, PMID:28905880). In silico tool predictions suggest damaging effect of the variant on gene or gene product(3CNET: 0.777>=0.75). A missense variant is a common mechanism associated with Leukodystrophy, hypomyelinating, 9. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Brisk reflexes (present) , Glaucoma (present) , Global developmental delay (present) , Hypertonia (present) , Macrotia (present) , Long toe (present) , Myopia (present) , … (more)
Brisk reflexes (present) , Glaucoma (present) , Global developmental delay (present) , Hypertonia (present) , Macrotia (present) , Long toe (present) , Myopia (present) , Secondary microcephaly (present) , Achilles tendon contracture (present) , Tip-toe gait (present) , Partial agenesis of the corpus callosum (present) (less)
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Likely pathogenic
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557765.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with hypomyelinating leukodystrophy, 9 (MIM#616140). Toxic gain of function has also been suggested (PMID: 31737794). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (119 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located adjacent in the annotated KMSKS motif, near a catalytic domain (PMID: 33515434, PMID: 28905880). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy. In one individual, the second variant was either due to a de novo event or non-paternity (PMID: 28905880, PMID: 31814314, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated protein mislocalization, increases in punctate structures and decreased phosphorylation of ribosomal S6 protein (PMID: 31737794), whereas transfected E.coli cells showed decreased aminoacetylation activity (PMID: 33515434). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Apr 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556868.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Jun 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004037846.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: RARS c.1367C>T (p.Ser456Leu) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein … (more)
Variant summary: RARS c.1367C>T (p.Ser456Leu) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 244948 control chromosomes in the gnomAD database, including 2 homozygotes. c.1367C>T has been reported in the literature in compound heterozygous individuals affected with PelizaeusMerzbacher disease (Nafinisia_2017) or mild hypomyelinating leukodystrophy (Mendes_2020), and the former had a truncating variant in trans. These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced aminoacylation activity and phosphorylation of ribosomal S6 protein, as well as disrupting protein localization and formation of myelin structures (Matsumoto_2019, Li_2021). The following publications have been ascertained in the context of this evaluation (PMID: 28905880, 31814314, 33515434, 31737794). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Benign
(Jan 02, 2024)
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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: SCV002508094.3
First in ClinVar: May 16, 2022 Last updated: Feb 14, 2024 |
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Uncertain significance
(Dec 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004936903.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.1367C>T (p.S456L) alteration is located in exon 12 (coding exon 12) of the RARS gene. This alteration results from a C to T substitution … (more)
The c.1367C>T (p.S456L) alteration is located in exon 12 (coding exon 12) of the RARS gene. This alteration results from a C to T substitution at nucleotide position 1367, causing the serine (S) at amino acid position 456 to be replaced by a leucine (L). This variant and a frameshift variant were identified in one individual with microcephaly, nystagmus, blindness, cognitive impairment, focal epilepsy, corpus callosum hypoplasia, and diffuse dysmyelination/hypomyelination of the central white matter; p.S456L was maternally inherited while the frameshift variant was not detected in either parent (Nafisinia, 2017). This variant was also identified with a another missense variant in a mildly affected individual with onset at two years of age and ability to walk without support; this individual did not have nystagmus, microcephaly, epilepsy, feeding difficulties, hypomyelination, or brain atrophy (Mendes, 2020). This variant formed punctate structures in 25% of cells compared wildtype in COS7 cells and failed to exhibit differentiated phenotypes with myelin web-like structures in FBD-102b cells (Matsumoto, 2019). The p.S456L alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypomyelinating leukodystrophy 9
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042670.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense c.1367C>T p.Ser456Leu variant in the RARS1 has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a … (more)
The missense c.1367C>T p.Ser456Leu variant in the RARS1 has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy Nafisinia, Michael et al.,2017. No published segregation evidence has been identified for this variant. This variant has moderate functional evidence supporting abnormal protein function Matsumoto, Naoto et al.,2019. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/ Likely Pathogenic multiple submissions. The amino acid Serine at position 456 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser456Leu in RARS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (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: SCV000322810.3
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
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Pathogenic
(Aug 20, 2019)
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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: SCV000851997.2
First in ClinVar: Oct 15, 2016 Last updated: Nov 08, 2019 |
Comment on evidence:
In a male patient with hypomyelinating leukodystrophy-9 (HLD9; 616140), born of first-cousin Turkish parents, Nafisinia et al. (2017) identified compound heterozygosity for 2 mutations in … (more)
In a male patient with hypomyelinating leukodystrophy-9 (HLD9; 616140), born of first-cousin Turkish parents, Nafisinia et al. (2017) identified compound heterozygosity for 2 mutations in the RARS gene: a c.1367C-T transition (c.1367C-T, NM_002887.3), resulting in a ser456-to-leu (S456L) substitution, and a 2-bp deletion (c.1846_1847delTA; 107820.0007), which resulted in a frameshift (Tyr61LeufsTer6) and a premature termination codon. Testing of the parents showed that the mother was heterozygous for the c.1376C-T mutation, whereas the father was variant negative, suggesting that the patient's deletion was either a de novo event or a consequence of nonpaternity. The patient was part of a cohort of 45 patients with a hypomyelinating disorder without a molecular diagnosis who were screened for mutation in the RARS gene. (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
HelpTitle | Author | Journal | Year | Link |
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Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease. | Li G | Science China. Life sciences | 2021 | PMID: 33515434 |
RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. | Mendes MI | Annals of clinical and translational neurology | 2020 | PMID: 31814314 |
Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. | Matsumoto N | Biochemistry and biophysics reports | 2019 | PMID: 31737794 |
Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. | Nafisinia M | European journal of human genetics : EJHG | 2017 | PMID: 28905880 |
Text-mined citations for rs139644798 ...
HelpRecord last updated May 12, 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.