ClinVar Genomic variation as it relates to human health
NM_020320.5(RARS2):c.3G>A (p.Met1Ile)
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.3G>A (p.Met1Ile)
Variation ID: 1070705 Accession: VCV001070705.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q15 6: 87589955 (GRCh38) [ NCBI UCSC ] 6: 88299673 (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 May 10, 2021 Feb 28, 2024 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020320.5:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_064716.2:p.Met1Ile missense initiator codon variant NM_001318785.2:c.-688G>A 5 prime UTR NM_001350505.2:c.3G>A NP_001337434.1:p.Met1Ile missense initiator codon variant NM_001350506.2:c.-744G>A 5 prime UTR NM_001350507.2:c.-867G>A 5 prime UTR NM_001350508.2:c.-906G>A 5 prime UTR NM_001350509.2:c.-614G>A 5 prime UTR NM_001350510.2:c.-744G>A 5 prime UTR NM_001350511.2:c.-863G>A 5 prime UTR NR_134857.2:n.33G>A non-coding transcript variant NR_146738.2:n.33G>A non-coding transcript variant NR_146739.2:n.33G>A non-coding transcript variant NR_146740.2:n.33G>A non-coding transcript variant NR_146741.2:n.33G>A non-coding transcript variant NR_146742.2:n.33G>A non-coding transcript variant NR_146743.2:n.33G>A non-coding transcript variant NR_146744.2:n.33G>A non-coding transcript variant NR_146745.2:n.33G>A non-coding transcript variant NR_146746.2:n.33G>A non-coding transcript variant NR_146747.2:n.33G>A non-coding transcript variant NR_146748.2:n.33G>A non-coding transcript variant NR_146749.2:n.33G>A non-coding transcript variant NR_146750.2:n.33G>A non-coding transcript variant NR_146751.2:n.33G>A non-coding transcript variant NR_146752.2:n.33G>A non-coding transcript variant NR_146753.2:n.33G>A non-coding transcript variant NR_146754.2:n.33G>A non-coding transcript variant NR_146755.2:n.33G>A non-coding transcript variant NR_146756.2:n.33G>A non-coding transcript variant NR_146757.2:n.33G>A non-coding transcript variant NR_146758.2:n.33G>A non-coding transcript variant NR_146759.2:n.33G>A non-coding transcript variant NC_000006.12:g.87589955C>T NC_000006.11:g.88299673C>T NG_008601.1:g.5063G>A - Protein change
- M1I
- Other names
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- Canonical SPDI
- NC_000006.12:87589954: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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
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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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RARS2 | - | - |
GRCh38 GRCh37 |
916 | 952 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV001382953.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 16, 2021 | RCV001797837.1 |
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
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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 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pontoneocerebellar hypoplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041760.2
First in ClinVar: Dec 25, 2021 Last updated: Sep 03, 2023 |
Comment:
Variant summary: RARS2 c.3G>A (p.Met1Ile) alters the initiation codon and an alternative downstream in-frame start codon (Met176) is located in exon 7 of the encoded … (more)
Variant summary: RARS2 c.3G>A (p.Met1Ile) alters the initiation codon and an alternative downstream in-frame start codon (Met176) is located in exon 7 of the encoded protein. It is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250948 control chromosomes (gnomAD). c.3G>A has been reported in the literature in at least one individual affected with prominent progressive action myoclonus (Courage_2021). Additionally, different variants (c.1A>T, c.1A>G) with disruption of this start codon were found in patients affected with Pontocerebellar hypoplasia (Lax_2015, Farwell_2015, Hou_2020, Bertoli-Avella_2021) and classified as pathogenic in ClinVar database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581914.5
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569). It has also been observed to segregate with disease in … (more)
Disruption of the initiator codon has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 26083569). It has also been observed to segregate with disease in related individuals. This sequence change affects the initiator methionine of the RARS2 mRNA. The next in-frame methionine is located at codon 176. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 1070705). This variant disrupts a region of the RARS2 protein in which other variant(s) (p.Gln12Arg) have been determined to be pathogenic (PMID: 20635367, 20952379, 22569581). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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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Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes. | Courage C | American journal of human genetics | 2021 | PMID: 33798445 |
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. | Helbig KL | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26795593 |
Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations. | Lax NZ | Journal of neuropathology and experimental neurology | 2015 | PMID: 26083569 |
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. | Farwell KD | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356970 |
Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. | Cassandrini D | Journal of inherited metabolic disease | 2013 | PMID: 22569581 |
Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. | Namavar Y | Brain : a journal of neurology | 2011 | PMID: 20952379 |
Pontocerebellar hypoplasia type 6: A British case with PEHO-like features. | Rankin J | American journal of medical genetics. Part A | 2010 | PMID: 20635367 |
Text-mined citations for rs2128238503 ...
HelpRecord 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.