ClinVar Genomic variation as it relates to human health
NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)
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(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)
Variation ID: 522814 Accession: VCV000522814.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.33 6: 30920091 (GRCh38) [ NCBI UCSC ] 6: 30887868 (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 Apr 29, 2018 Jun 17, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020442.6:c.1168G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065175.4:p.Ala390Thr missense NM_001167733.3:c.748G>A NP_001161205.1:p.Ala250Thr missense NM_001167734.2:c.1258G>A NP_001161206.1:p.Ala420Thr missense NC_000006.12:g.30920091G>A NC_000006.11:g.30887868G>A NG_034224.1:g.10884G>A - Protein change
- A390T, A420T, A250T
- Other names
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- Canonical SPDI
- NC_000006.12:30920090:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Decreased function
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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 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00012
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00031
The Genome Aggregation Database (gnomAD) 0.00039
The Genome Aggregation Database (gnomAD), exomes 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00065
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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VARS2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
392 | 485 |
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
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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Dec 18, 2023 | RCV000625984.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 22, 2024 | RCV000676486.27 | |
See cases
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2020 | RCV002252181.4 |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 11, 2021 | RCV002529769.4 | |
VARS2-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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May 9, 2023 | RCV004547763.1 |
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
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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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 20
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001137065.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Dec 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523926.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: BS1
Clinical Features:
Short stature (present) , Neurodevelopmental abnormality (present) , Autistic behavior (present) , Abnormality of mental function (present) , Abnormal facial shape (present)
Geographic origin: Brazil
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Likely pathogenic
(Nov 06, 2023)
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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: SCV001987432.5
First in ClinVar: Nov 06, 2021 Last updated: Nov 25, 2023 |
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: 33937156, … (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: 33937156, 34484863, 31623496, 29314548, 30458719, 34216551) (less)
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Pathogenic
(Jan 22, 2024)
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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: SCV002304175.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the VARS2 protein (p.Ala420Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the VARS2 protein (p.Ala420Thr). This variant is present in population databases (rs202201763, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of VARS2-related conditions (PMID: 29314548, 33937156; Invitae). 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: 522814). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Aug 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003681574.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
Bruni, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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Uncertain significance
(Aug 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002586104.11
First in ClinVar: Oct 22, 2022 Last updated: Jun 17, 2024 |
Comment:
VARS2: PM3, PM2:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(May 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 20
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746589.1 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Comment:
This variant was found in trans with another variant (c.1076-14A>G) in a 6-year-old male with severe neurodevelopmental impairment, encephalopathy, microcephaly, hypertrophic cardiomyopathy, lactic acidosis, seizure … (more)
This variant was found in trans with another variant (c.1076-14A>G) in a 6-year-old male with severe neurodevelopmental impairment, encephalopathy, microcephaly, hypertrophic cardiomyopathy, lactic acidosis, seizure disorder (infantile spasms), abnormal MRI showing brain and brainstem atrophy. (less)
Number of individuals with the variant: 1
Clinical Features:
Unilateral cryptorchidism (present) , Small nail (present) , Short stature (present) , Severe global developmental delay (present) , Respiratory failure (present) , Primary Caesarian section … (more)
Unilateral cryptorchidism (present) , Small nail (present) , Short stature (present) , Severe global developmental delay (present) , Respiratory failure (present) , Primary Caesarian section (present) , Premature birth (present) , Muscular hypotonia of the trunk (present) , Limb hypertonia (present) , Lacticaciduria (present) , Infantile spasms (present) , Increased serum lactate (present) , Hypospadias (present) , Generalized myoclonic seizures (present) , Failure to thrive (present) , Elevated urinary 3-hydroxybutyric acid (present) , Elevated brain lactate level by MRS (present) , Downslanted palpebral fissures (present) , Developmental regression (present) , Congenital bilateral ptosis (present) , Cerebral white matter atrophy (present) , Cerebellar atrophy (present) , Cardiomegaly (present) , Caesarian section (present) , Abnormal maternal serum screening (present) , 2-3 toe syndactyly (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hispanic
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-05-04
Testing laboratory interpretation: Uncertain significance
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Likely pathogenic
(May 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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VARS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119278.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The VARS2 c.1258G>A variant is predicted to result in the amino acid substitution p.Ala420Thr. This variant was reported in the homozygous state in two siblings … (more)
The VARS2 c.1258G>A variant is predicted to result in the amino acid substitution p.Ala420Thr. This variant was reported in the homozygous state in two siblings and an apparently unrelated individual with VARS2-related mitochondrial disease (Bruni et al 2018. PubMed ID: 29314548). This variant was also reported, with alternative nomenclature (NM_020442.6:c.1168G>A; p.Ala390Thr), in the compound heterozygous state in a fourth individual with a related phenotype. (Kušíková K et al 2021. PubMed ID: 33937156). Experimental studies on muscle homogenate from this patient indicated that VARS2 protein was deficient. This variant is reported in 0.24% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-30887868-G-A). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 20
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241293.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: VARS2 c.1168G>A (p.Ala390Thr) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein … (more)
Variant summary: VARS2 c.1168G>A (p.Ala390Thr) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 1534628 control chromosomes (gnomAD V4.0). The variant, c.1168G>A (aka. c.1258G>A, p.Ala420Thr), has been reported in the literature in multiple individuals affected with Combined Oxidative Phosphorylation Defect Type 20 (Bruni_2018, Kusikova_2021). One of these publications reported that VARS2 protein was deficient in patient derived muscle biopsy, and the resulting defect of oxidative phosphorylation was also demonstrated by enzymatic assay (Kusikova_2021). 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: 29314548, 33937156, 34216551). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Oct 25, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802269.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jul 10, 2020)
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no assertion criteria provided
Method: literature only
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COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 20
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001372473.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment on evidence:
In 3 patients (P8, P9, P10) from 2 unrelated Mexican families (families 7 and 8) with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. … (more)
In 3 patients (P8, P9, P10) from 2 unrelated Mexican families (families 7 and 8) with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified homozygosity for a c.1258G-A transition (c.1258G-A, NM_001167734.1) in the VARS2 gene, resulting in an ala420-to-thr (A420T) substitution in a region important for the interaction of VARS2 with the cognate mRNA. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. The A420T variant had a frequency of 0.0312% in the ExAC database. Functional studies were not performed. The patients had infantile-onset hypertrophic cardiomyopathy, elevated plasma lactate, and hypotonia. (less)
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Pathogenic
(Feb 22, 2021)
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no assertion criteria provided
Method: clinical testing
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Combined oxidative phosphorylation defect type 20
(Autosomal recessive inheritance)
Affected status: not applicable
Allele origin:
not applicable
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Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University
Accession: SCV001481167.1
First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Sex: male
Tissue: muscle
Result:
(1) Enzymatic activity of respiratory chain complex I was reduced in muscle. (2) Protein amount of respiratory chain complexes I (subunit NDUFS4), III (subunit UQCRC2), and IV (MT-CO2) were reduced in muscle. (3) Immunohistochemical staining of complexes I (subunit NDUFB8) and III (subunit UQCRC2) was reduced.
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Decreased function
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Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University
Accession: SCV001481167.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Targeted long-read sequencing identifies missing disease-causing variation. | Miller DE | American journal of human genetics | 2021 | PMID: 34216551 |
Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy. | Kušíková K | Frontiers in pediatrics | 2021 | PMID: 33937156 |
Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. | Bruni F | Human mutation | 2018 | PMID: 29314548 |
Text-mined citations for rs202201763 ...
HelpRecord last updated Jun 17, 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.