This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5.
ClinVar Genomic variation as it relates to human health
NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)
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.
(11)
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.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020745.4(AARS2):c.595C>T (p.Arg199Cys)
Variation ID: 213963 Accession: VCV000213963.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 44311148 (GRCh38) [ NCBI UCSC ] 6: 44278885 (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 Dec 19, 2017 Oct 13, 2024 Jul 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020745.4:c.595C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065796.2:p.Arg199Cys missense NC_000006.12:g.44311148G>A NC_000006.11:g.44278885G>A NG_031952.1:g.7179C>T Q5JTZ9:p.Arg199Cys - Protein change
- R199C
- Other names
- -
- Canonical SPDI
- NC_000006.12:44311147:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00012
- 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. |
|||
| AARS2 | - | - |
GRCh38 GRCh37 |
439 | 593 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2024 | RCV000239768.21 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 30, 2019 | RCV001195936.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2021 | RCV001808557.6 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 13, 2022 | RCV002515373.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 15, 2021 | RCV001775096.2 |
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
(Jan 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation defect type 8
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366360.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5.
|
|
|
Likely pathogenic
(Sep 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Combined oxidative phosphorylation defect type 8
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001524648.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
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Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019230.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Likely pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003707633.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.595C>T (p.R199C) alteration is located in exon 4 (coding exon 4) of the AARS2 gene. This alteration results from a C to T substitution … (more)
The c.595C>T (p.R199C) alteration is located in exon 4 (coding exon 4) of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 595, causing the arginine (R) at amino acid position 199 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (26/282578) total alleles studied. The highest observed frequency was 0.02% (23/128984) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in trans with an AARS2 pathogenic mutation, in multiple individuals with mitochondrial alanyl-tRNA synthetase deficiency (Szpisjak, 2017; Carle, 2018; Lynch, 2016; Taglia, 2018; Srivastava, 2019; Xie, 2020; Cohen, 2022; Dallabona, 2014). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Mar 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Leukoencephalopathy, progressive, with ovarian failure
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002576465.5
First in ClinVar: Oct 01, 2022 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Clinical Features:
Confusion (present) , Leukodystrophy (present)
Sex: female
|
|
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Pathogenic
(Aug 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000862734.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Pathogenic
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Generalized muscle weakness
Affected status: yes
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV002012461.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
|
|
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Pathogenic
(May 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Leukoencephalopathy, progressive, with ovarian failure
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059713.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002149823.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs200105202, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the … (more)
This variant is present in population databases (rs200105202, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213963). This missense change has been observed in individual(s) with leukoencephalopathy (PMID: 24808023, 27749956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the AARS2 protein (p.Arg199Cys). (less)
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Pathogenic
(Jul 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000250986.12
First in ClinVar: Oct 11, 2015 Last updated: Sep 16, 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: 25705216, … (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: 25705216, 27734837, 29749055, 31920941, 31099476, 27749956, 31885218, 24808023, 31980526, 31589614, 33144682, 34784527, 35305867, 29971983, 30706699, 36732629, 38253606) (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Combined oxidative phosphorylation defect type 8
Affected status: unknown
Allele origin:
maternal
|
GenomeConnect, ClinGen
Accession: SCV002075014.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 11-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 11-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of eye movement (present) , Hearing impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of the musculature of the … (more)
Abnormality of eye movement (present) , Hearing impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of the musculature of the limbs (present) , Abnormal esophagus morphology (present) , Recurrent infections (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2020-11-10
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.595C>T (p.R199C) alteration is located in exon 4 (coding exon 4) of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 595, causing the arginine (R) at amino acid position 199 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (26/282578) total alleles studied. The highest observed frequency was 0.02% (23/128984) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in trans with an AARS2 pathogenic mutation, in multiple individuals with mitochondrial alanyl-tRNA synthetase deficiency (Szpisjak, 2017; Carle, 2018; Lynch, 2016; Taglia, 2018; Srivastava, 2019; Xie, 2020; Cohen, 2022; Dallabona, 2014). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Comment:
This variant is present in population databases (rs200105202, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213963). This missense change has been observed in individual(s) with leukoencephalopathy (PMID: 24808023, 27749956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the AARS2 protein (p.Arg199Cys).
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: 25705216, 27734837, 29749055, 31920941, 31099476, 27749956, 31885218, 24808023, 31980526, 31589614, 33144682, 34784527, 35305867, 29971983, 30706699, 36732629, 38253606)
Comment:
Variant interpreted as Pathogenic and reported on 11-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5.
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.595C>T (p.R199C) alteration is located in exon 4 (coding exon 4) of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 595, causing the arginine (R) at amino acid position 199 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (26/282578) total alleles studied. The highest observed frequency was 0.02% (23/128984) of European (non-Finnish) alleles. This alteration has been detected in the homozygous state, and in trans with an AARS2 pathogenic mutation, in multiple individuals with mitochondrial alanyl-tRNA synthetase deficiency (Szpisjak, 2017; Carle, 2018; Lynch, 2016; Taglia, 2018; Srivastava, 2019; Xie, 2020; Cohen, 2022; Dallabona, 2014). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Comment:
This variant is present in population databases (rs200105202, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213963). This missense change has been observed in individual(s) with leukoencephalopathy (PMID: 24808023, 27749956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the AARS2 protein (p.Arg199Cys).
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: 25705216, 27734837, 29749055, 31920941, 31099476, 27749956, 31885218, 24808023, 31980526, 31589614, 33144682, 34784527, 35305867, 29971983, 30706699, 36732629, 38253606)
Comment:
Variant interpreted as Pathogenic and reported on 11-10-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes. | Cohen ASA | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35305867 |
| New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies. | Xie JJ | CNS neuroscience & therapeutics | 2020 | PMID: 31885218 |
| Expansion of the clinical spectrum associated with AARS2-related disorders. | Srivastava S | American journal of medical genetics. Part A | 2019 | PMID: 31099476 |
| Alanyl-tRNA Synthetase 2-Related Dementia with Selective Bilateral Frontal Cystic Leukoencephalopathy. | Carle G | Journal of clinical neurology (Seoul, Korea) | 2018 | PMID: 29971983 |
| AARS2-related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases. | Taglia I | Acta neurologica Scandinavica | 2018 | PMID: 29749055 |
| Novel AARS2 gene mutation producing leukodystrophy: a case report. | Szpisjak L | Journal of human genetics | 2017 | PMID: 27734837 |
| Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia. | Lynch DS | JAMA neurology | 2016 | PMID: 27749956 |
| Novel (ovario) leukodystrophy related to AARS2 mutations. | Dallabona C | Neurology | 2014 | PMID: 24808023 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AARS2 | - | - | - | - |
Text-mined citations for rs200105202 ...
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 Oct 20, 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.