ClinVar Genomic variation as it relates to human health
NM_020320.5(RARS2):c.110+5A>G
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_020320.5(RARS2):c.110+5A>G
Variation ID: 891 Accession: VCV000000891.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q15 6: 87569512 (GRCh38) [ NCBI UCSC ] 6: 88279230 (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 9, 2016 Apr 15, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020320.5:c.110+5A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001318785.2:c.-360+5A>G intron variant NM_001350505.2:c.110+5A>G intron variant NM_001350506.2:c.-416+5A>G intron variant NM_001350507.2:c.-416+5A>G intron variant NM_001350508.2:c.-578+5A>G intron variant NM_001350509.2:c.-359-5280A>G intron variant NM_001350510.2:c.-416+5A>G intron variant NM_001350511.2:c.-535+5A>G intron variant NC_000006.12:g.87569512T>C NC_000006.11:g.88279230T>C NG_008601.1:g.25506A>G - Protein change
- Other names
- IVS2, A-G, +5
- Canonical SPDI
- NC_000006.12:87569511:T:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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RARS2 | - | - |
GRCh38 GRCh37 |
879 | 915 |
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
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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, multiple submitters, no conflicts
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Jul 25, 2023 | RCV000000939.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV001093189.22 |
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
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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
(Apr 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002779363.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 6
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208435.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 24, 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: SCV001392766.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 2 of the RARS2 gene. It does not directly change the encoded amino acid sequence of the RARS2 protein. … (more)
This sequence change falls in intron 2 of the RARS2 gene. It does not directly change the encoded amino acid sequence of the RARS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs63749985, gnomAD 0.003%). This variant has been observed in individuals with pontocerebellar hypoplasia (PMID: 17847012, 26970947). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+5A>G. ClinVar contains an entry for this variant (Variation ID: 891). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 2 skipping and introduces a premature termination codon (PMID: 17847012). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2019)
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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: SCV001250047.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2007)
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no assertion criteria provided
Method: literature only
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PONTOCEREBELLAR HYPOPLASIA, TYPE 6
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021089.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016 |
Comment on evidence:
In affected members of a consanguineous Sephardic Jewish family with a form of pontocerebellar hypoplasia (PCH6; 611523), Edvardson et al. (2007) detected homozygosity for an … (more)
In affected members of a consanguineous Sephardic Jewish family with a form of pontocerebellar hypoplasia (PCH6; 611523), Edvardson et al. (2007) detected homozygosity for an A-to-G transition at the +5 position of intron 2 of the RARS2 gene (IVS2+5A-G). The parents and 2 unaffected sibs were carriers for the mutation. Major transcript from 1 patient lacked exon 2, but a faint normal-sized fragment was also seen on PCR amplification. Because exon 2 consists of 74 nucleotides, its skipping was predicted to cause frameshift, abolishing enzymatic activity entirely. A striking reduction in the amount of mitochondrial tRNA(arg) was found in patient fibroblasts, and the tRNA(arg):tRNA(leu) ratio was 6% of the control value. (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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RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia. | Nishri D | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2016 | PMID: 26970947 |
Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. | Edvardson S | American journal of human genetics | 2007 | PMID: 17847012 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs63749985 ...
HelpRecord last updated Apr 15, 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.
ClinGen staff contributed the HGVS expression for this variant.