ClinVar Genomic variation as it relates to human health
NM_015836.4(WARS2):c.938A>T (p.Lys313Met)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015836.4(WARS2):c.938A>T (p.Lys313Met)
Variation ID: 440917 Accession: VCV000440917.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p12 1: 119033056 (GRCh38) [ NCBI UCSC ] 1: 119575679 (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 16, 2017 Apr 15, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015836.4:c.938A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056651.1:p.Lys313Met missense NM_001378226.1:c.869A>T NP_001365155.1:p.Lys290Met missense NM_001378227.1:c.869A>T NP_001365156.1:p.Lys290Met missense NM_001378228.1:c.767A>T NP_001365157.1:p.Lys256Met missense NM_001378229.1:c.680A>T NP_001365158.1:p.Lys227Met missense NM_001378230.1:c.656A>T NP_001365159.1:p.Lys219Met missense NM_001378231.1:c.*273A>T 3 prime UTR NM_201263.2:c.*304A>T 3 prime UTR NC_000001.11:g.119033056T>A NC_000001.10:g.119575679T>A NG_050658.1:g.112733A>T - Protein change
- K313M, K219M, K227M, K256M, K290M
- Other names
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- Canonical SPDI
- NC_000001.11:119033055:T: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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00024
1000 Genomes Project 30x 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00034
The Genome Aggregation Database (gnomAD) 0.00035
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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WARS2 | - | - |
GRCh38 GRCh37 |
124 | 163 |
Conditions - Germline
Condition
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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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Likely pathogenic (2) |
criteria provided, single submitter
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Mar 30, 2023 | RCV000509075.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 26, 2014 | RCV000622962.5 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2023 | RCV001726205.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2023 | RCV003323579.3 |
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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Likely pathogenic
(Jan 23, 2018)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002064342.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Dec 26, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740757.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability, severe (present) , Global developmental delay (present) , Generalized tonic-clonic seizures (present) , Muscular hypotonia (present) , Inability to walk (present) , Movement … (more)
Intellectual disability, severe (present) , Global developmental delay (present) , Generalized tonic-clonic seizures (present) , Muscular hypotonia (present) , Inability to walk (present) , Movement disorder (present) , Tremor (present) , Obstructive sleep apnea syndrome (present) , Status epilepticus (present) , Menorrhagia (present) , Cortical visual impairment (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
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Pathogenic
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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WARS2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004029151.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Variant summary: WARS2 c.938A>T (p.Lys313Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: WARS2 c.938A>T (p.Lys313Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251486 control chromosomes (gnomAD). c.938A>T has been reported in the literature as a compound heterozygous genotype in multiple extensively genotyped individuals affected with WARS2-Related Disorders, primarily presenting with a combination of leukoencephalopathy, developmental delay, abnormal movements and lactic acidosis, and it has been found to segregate with the disorder in an autosomal recessive inheritance pattern within families (e.g. Theisen_2017, Wortmann_2017, Vantroys_2018, Maffezzini_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30920170, 28650581, 29783990, 28905505). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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WARS2-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046114.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a compound heterozygous change in patients with WARS2 -related disorders (PMID: 28650581, 28905505, 30920170, 31282308, 35074316). Functional studies … (more)
This variant has been previously reported as a compound heterozygous change in patients with WARS2 -related disorders (PMID: 28650581, 28905505, 30920170, 31282308, 35074316). Functional studies showed that the c.938A>T (p.Lys313Met) variant alters the function of the WARS2 protein (PMID: 28650581, 28905505, 30920170). The c.938A>T (p.Lys313Met) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.024% (69/282894) and is absent in the homozygous state, thus is presumed to be rare. The c.938A>T (p.Lys313Met) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.938A>T (p.Lys313Met) variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Nov 17, 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: SCV002222940.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 313 of the WARS2 protein (p.Lys313Met). … (more)
This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 313 of the WARS2 protein (p.Lys313Met). This variant is present in population databases (rs145867327, gnomAD 0.05%). This missense change has been observed in individuals with WARS2-related leukoencephalopathy (PMID: 28650581, 28905505, 29783990, 30920170, 31282308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 440917). 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 not expected to disrupt WARS2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812364.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in WARS2 is predicted to replace lysine with methionine at codon 313, p.(Lys313Met). The lysine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in WARS2 is predicted to replace lysine with methionine at codon 313, p.(Lys313Met). The lysine residue is highly conserved (100 vertebrates, UCSC), and is located in an helical region. There is a moderate physicochemical difference between lysine and methionine. The highest population minor allele frequency in gnomAD v2.1 is 0.05% (61/129,200 alleles) in the European (non-Finnish) population, which is conistent with a recessive condition. This variant has been detected in at least six individuals with early onset complex neurodevelopmental disorders. Of those individuals, three individuals were compound heterozygous for the variant and a likely pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 28650581, 28905505, 29783990, 30920170, 31282308). The variant has been reported to segregate with disease in at least two families (PMID: 28905505, 30920170). At least three patient's with this variant displayed oxidative phophorylation complex analyses conistent with a defect in mitochondrial gene expression in patient cells (PMID: 28650581, 29783990, 30920170). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Moderate, PM2_Supporting, PP4. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963564.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972461.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Feb 17, 2022)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000606856.2
First in ClinVar: Oct 16, 2017 Last updated: Feb 20, 2022 |
Comment on evidence:
In a 24-year-old man with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with seizures (NEMMLAS; 617710), Theisen et al. (2017) identified compound heterozygous … (more)
In a 24-year-old man with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis, with seizures (NEMMLAS; 617710), Theisen et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion, resulting in a lys313-to-met (K313M) substitution at a conserved residue, and a 3-bp in-frame deletion (c.298_300delCTT; 604733.0004), resulting in the deletion of leu100 at a conserved residue in the catalytic core domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The K313M variant was found at a low frequency in the ExAC database (18 of 121,412 alleles, 0.0001483) and the gnomAD database (74 of 282,690 alleles, 2.62 x 10(-4)). However, it was not found in homozygous state. Patient fibroblasts showed decreased de novo synthesis of proteins within the mitochondria, leading to significantly decreased steady-state levels of respiratory chain subunits and lower oxygen consumption rates compared to controls (about 30%). In 2 boys, born of unrelated Dutch parents (family F2), with NEMMLAS, Wortmann et al. (2017) identified compound heterozygous mutations in the WARS2 gene: a c.938A-T transversion in exon 6, resulting in a lys313-to-met (K313M) substitution at a highly conserved residue in the anti-codon recognition domain, and a 1-bp deletion in exon 6 (c.797delC; 604733.0005), resulting in a frameshift and premature termination (Pro266ArgfsTer10). An unrelated patient (I6), born of unrelated Canadian parents (family F5), without seizures was compound heterozygous for K313M and a c.134G-T transversion in exon 2, resulting in a gly45-to-val (G45V; 604733.0006) substitution at a conserved residue within a small loop that covers the tRNA binding site. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. They were filtered against the dbSNP (build 137) and gnomAD databases. In the gnomAD database, the K313M and c.797delC variants were found at low frequencies (0.0001407 and 4.07 x 10(-5), respectively), and the G45V variant was not listed. Studies of patient cells showed that the K313M mutant protein was sensitive to proteolytic degradation. In 2 sisters, born of unrelated Swedish parents, with NEMMLAS, Maffezzini et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: K313M and a c.833T-G transversion, resulting in a val278-to-gly (V278G; 604733.0010) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both were found at low frequencies in the gnomAD database (1.5 x 10(-4) for K313M and 2.4 x 10(-4) for V278G). Expression of the corresponding mutations in wars2-null yeast showed variable growth defects and impaired mitochondrial respiration. Patient fibroblasts showed a reduction in fully aminoacylated tRNA(Trp), but there was not a decrease in mitochondrial respiration. However, patient fibroblasts reprogrammed into neuroepithelial cells confirmed the aminoacylation defect and showed a defect in mitochondrial gene expression, decreased oxygen consumption, and decreased activities of complexes I and IV, suggesting impaired mitochondrial function. In a 22-year-old Swedish woman with NEMMLAS, Ilinca et al. (2022) identified compound heterozygosity for the K313M and V278G mutations in the WARS2 gene. She had onset of persistent epilepsy in the neonatal period and Levodopa-responsive parkinsonism. Functional studies of the variant and studies of patient cells were not performed. (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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A relatively common hypomorphic variant in WARS2 causes monogenic disease. | Ilinca A | Parkinsonism & related disorders | 2022 | PMID: 35074316 |
Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase. | Virdee M | Journal of child neurology | 2019 | PMID: 31282308 |
Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy. | Maffezzini C | Molecular genetics & genomic medicine | 2019 | PMID: 30920170 |
Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency. | Vantroys E | Orphanet journal of rare diseases | 2018 | PMID: 29783990 |
Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. | Wortmann SB | Human mutation | 2017 | PMID: 28905505 |
Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. | Theisen BE | American journal of medical genetics. Part A | 2017 | PMID: 28650581 |
Text-mined citations for rs145867327 ...
HelpRecord last updated Apr 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.