In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27061686, 29431110, 34717047, 33209735, 24047924)
ClinVar Genomic variation as it relates to human health
NM_020320.5(RARS2):c.773G>A (p.Arg258His)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Likely pathogenic(5); Uncertain significance(2)
Likely pathogenic(5); Uncertain significance(2)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020320.5(RARS2):c.773G>A (p.Arg258His)
Variation ID: 215080 Accession: VCV000215080.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q15 6: 87529647 (GRCh38) [ NCBI UCSC ] 6: 88239365 (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 Sep 30, 2017 Nov 24, 2024 Nov 12, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020320.5:c.773G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_064716.2:p.Arg258His missense NM_001318785.2:c.248G>A NP_001305714.1:p.Arg83His missense NM_001350505.2:c.773G>A NP_001337434.1:p.Arg258His missense NM_001350506.2:c.248G>A NP_001337435.1:p.Arg83His missense NM_001350507.2:c.248G>A NP_001337436.1:p.Arg83His missense NM_001350508.2:c.248G>A NP_001337437.1:p.Arg83His missense NM_001350509.2:c.248G>A NP_001337438.1:p.Arg83His missense NM_001350510.2:c.248G>A NP_001337439.1:p.Arg83His missense NM_001350511.2:c.248G>A NP_001337440.1:p.Arg83His missense NR_134857.2:n.803G>A non-coding transcript variant NR_146738.2:n.1071G>A non-coding transcript variant NR_146739.2:n.884G>A non-coding transcript variant NR_146740.2:n.1148G>A non-coding transcript variant NR_146741.2:n.810G>A non-coding transcript variant NR_146742.2:n.1186G>A non-coding transcript variant NR_146743.2:n.1024G>A non-coding transcript variant NR_146744.2:n.1148G>A non-coding transcript variant NR_146745.2:n.807G>A non-coding transcript variant NR_146746.2:n.1242G>A non-coding transcript variant NR_146747.2:n.586G>A non-coding transcript variant NR_146748.2:n.1024G>A non-coding transcript variant NR_146749.2:n.1024G>A non-coding transcript variant NR_146750.2:n.1148G>A non-coding transcript variant NR_146751.2:n.1024G>A non-coding transcript variant NR_146752.2:n.1092G>A non-coding transcript variant NR_146753.2:n.940G>A non-coding transcript variant NR_146754.2:n.884G>A non-coding transcript variant NR_146755.2:n.1148G>A non-coding transcript variant NR_146756.2:n.803G>A non-coding transcript variant NR_146757.2:n.1074G>A non-coding transcript variant NR_146758.2:n.807G>A non-coding transcript variant NR_146759.2:n.807G>A non-coding transcript variant NC_000006.12:g.87529647C>T NC_000006.11:g.88239365C>T NG_008601.1:g.65371G>A - Protein change
- R258H, R83H
- Other names
- -
- Canonical SPDI
- NC_000006.12:87529646: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00024
The Genome Aggregation Database (gnomAD), exomes 0.00028
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00039
The Genome Aggregation Database (gnomAD) 0.00044
1000 Genomes Project 30x 0.00016
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| RARS2 | - | - |
GRCh38 GRCh37 |
919 | 955 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Nov 12, 2024 | RCV000727871.30 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 30, 2024 | RCV000765897.9 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Jun 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000855363.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Likely pathogenic
(Nov 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000252183.8
First in ClinVar: Oct 11, 2015 Last updated: Nov 24, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27061686, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27061686, 29431110, 34717047, 33209735, 24047924) (less)
|
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Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 6
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000897317.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Likely pathogenic
(Nov 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 6
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244487.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PM3_Strong, PM1
|
|
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Likely pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002975713.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RARS2 protein (p.Arg258His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RARS2 protein (p.Arg258His). This variant is present in population databases (rs145297855, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RARS2-related conditions (PMID: 24047924, 33209735). 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. ClinVar contains an entry for this variant (Variation ID: 215080). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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|
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Likely pathogenic
(Mar 30, 2024)
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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
|
Baylor Genetics
Accession: SCV004206131.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Likely pathogenic
(Jan 01, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497443.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Comment:
RARS2: PM2, PM3, PP1, PP3
Number of individuals with the variant: 2
|
|
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Uncertain significance
(Jan 20, 2020)
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no assertion criteria provided
Method: clinical testing
|
Pontocerebellar hypoplasia, type 6
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002079904.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
PM3_Strong, PM1
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RARS2 protein (p.Arg258His). This variant is present in population databases (rs145297855, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RARS2-related conditions (PMID: 24047924, 33209735). 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. ClinVar contains an entry for this variant (Variation ID: 215080). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
RARS2: PM2, PM3, PP1, PP3
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. |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27061686, 29431110, 34717047, 33209735, 24047924)
Comment:
PM3_Strong, PM1
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RARS2 protein (p.Arg258His). This variant is present in population databases (rs145297855, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RARS2-related conditions (PMID: 24047924, 33209735). 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. ClinVar contains an entry for this variant (Variation ID: 215080). 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 disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
RARS2: PM2, PM3, PP1, PP3
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A term neonate with early myoclonic encephalopathy caused by RARS2 gene variants: a case report. | Xu Y | Translational pediatrics | 2020 | PMID: 33209735 |
| Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. | Kastrissianakis K | Archives of disease in childhood | 2013 | PMID: 24047924 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RARS2 | - | - | - | - |
Text-mined citations for rs145297855 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.