ClinVar Genomic variation as it relates to human health
NM_006567.5(FARS2):c.667C>T (p.Arg223Cys)
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.
Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006567.5(FARS2):c.667C>T (p.Arg223Cys)
Variation ID: 214330 Accession: VCV000214330.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p25.1 6: 5404596 (GRCh38) [ NCBI UCSC ] 6: 5404829 (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 29, 2016 Mar 4, 2023 Aug 12, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006567.5:c.667C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006558.1:p.Arg223Cys missense NM_001318872.2:c.667C>T NP_001305801.1:p.Arg223Cys missense NM_001374875.1:c.667C>T NP_001361804.1:p.Arg223Cys missense NM_001374876.1:c.667C>T NP_001361805.1:p.Arg223Cys missense NM_001374877.1:c.667C>T NP_001361806.1:p.Arg223Cys missense NM_001374878.1:c.667C>T NP_001361807.1:p.Arg223Cys missense NM_001374879.1:c.667C>T NP_001361808.1:p.Arg223Cys missense NM_001375257.1:c.667C>T NP_001362186.1:p.Arg223Cys missense NM_001375258.1:c.667C>T NP_001362187.1:p.Arg223Cys missense NM_001375259.1:c.-30C>T 5 prime UTR NM_001375260.1:c.-30C>T 5 prime UTR NC_000006.12:g.5404596C>T NC_000006.11:g.5404829C>T NG_033003.2:g.148246C>T - Protein change
- R223C
- Other names
- p.R223C:CGC>TGC
- Canonical SPDI
- NC_000006.12:5404595: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
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Exome Aggregation Consortium (ExAC) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00026
The Genome Aggregation Database (gnomAD) 0.00028
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
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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FARS2 | - | - |
GRCh38 GRCh37 |
321 | 602 |
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. |
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Uncertain significance (2) |
criteria provided, single submitter
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Dec 17, 2020 | RCV000196357.5 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 12, 2022 | RCV000650594.10 |
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
(Apr 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 14
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164195.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Uncertain significance
(Aug 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 14
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000772441.7
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 223 of the FARS2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 223 of the FARS2 protein (p.Arg223Cys). This variant is present in population databases (rs202060864, gnomAD 0.2%). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 32597768). ClinVar contains an entry for this variant (Variation ID: 214330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FARS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Dec 17, 2020)
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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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GeneDx
Accession: SCV000251370.13
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 32597768)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549974.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FARS2 p.Arg223Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs202060864), … (more)
The FARS2 p.Arg223Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs202060864), ClinVar (classified as likely pathogenic by GeneDx and uncertain significance by Invitae. The variant was identified in control databases in 76 of 281418 chromosomes at a frequency of 0.0002701 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 47 of 25106 chromosomes (freq: 0.001872), Ashkenazi Jewish in 10 of 10350 chromosomes (freq: 0.000966), European (non-Finnish) in 17 of 128836 chromosomes (freq: 0.000132) and African in 2 of 24928 chromosomes (freq: 0.00008), but was not observed in the Latino, East Asian, Other or South Asian populations. The p.Arg223 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Early-onset epileptic encephalopathy with migrating focal seizures associated with a FARS2 homozygous nonsense variant. | Ville D | Epileptic disorders : international epilepsy journal with videotape | 2020 | PMID: 32597768 |
Text-mined citations for rs202060864 ...
HelpRecord last updated Feb 04, 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.