ClinVar Genomic variation as it relates to human health
NM_152268.4(PARS2):c.283G>A (p.Val95Ile)
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(4); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_152268.4(PARS2):c.283G>A (p.Val95Ile)
Variation ID: 432121 Accession: VCV000432121.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p32.3 1: 54758879 (GRCh38) [ NCBI UCSC ] 1: 55224552 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Aug 20, 2017 Jul 23, 2024 Mar 17, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_152268.4:c.283G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689481.2:p.Val95Ile missense NC_000001.11:g.54758879C>T NC_000001.10:g.55224552C>T NG_042048.1:g.10675G>A - Protein change
- V95I
- Other names
-
PARS2, VAL95ILE (rs147227819)
- Canonical SPDI
- NC_000001.11:54758878:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00100 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00013
1000 Genomes Project 30x 0.00094
1000 Genomes Project 0.00100
- 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. |
|||
| PARS2 | - | - |
GRCh38 GRCh37 |
156 | 174 | |
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 (2) |
criteria provided, conflicting classifications
|
Sep 7, 2022 | RCV000497433.8 | |
|
PARS2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 26, 2018 | RCV000723278.1 |
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Mar 17, 2024 | RCV000779609.16 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Oct 01, 2019)
|
criteria provided, single submitter
Method: curation
|
Developmental and epileptic encephalopathy, 75
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV001146819.1
First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
Comment:
This variant is interpreted as a variant of uncertain significance for Epileptic encephalopathy, early infantile, 75, autosomal recessive. The following ACMG Tag(s) were applied: PM2, … (more)
This variant is interpreted as a variant of uncertain significance for Epileptic encephalopathy, early infantile, 75, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PM3. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 75
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426434.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 75
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV002073813.1
First in ClinVar: Feb 09, 2022 Last updated: Feb 09, 2022 |
Number of individuals with the variant: 2
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
|
Uncertain significance
(Jul 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589806.5
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28077841, 29915213, 32071833, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28077841, 29915213, 32071833, 30237576, 31130284, 31487502, 32514400, 34426522, 32533790, 32860008, 34484863, 34585293, Franz2020[paper], 34645488) (less)
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental and epileptic encephalopathy, 75
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557055.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 75 (MIM#618437). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated dimerization domain (NCBI, PMID: 29915213). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described once as a VUS, but more recently and consistently as pathogenic and likely pathogenic in many unrelated homozygous and compound heterozygous individuals with infantile-onset epileptic encephalopathy, microcephaly, intellectual disability, seizures and/or mitochondrial disease (ClinVar, PMID: 31130284, PMID: 32071833, PMID: 30237576, PMID: 28077841, PMID: 29915213, PMID: 32533790, PMID: 32514400). (SP) 0902 - This variant has moderate evidence for segregation with disease. It was observed in a combined total of four affected siblings in two unrelated families with infantile-onset epileptic encephalopathy (PMID: 28077841, PMID: 29915213). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Sep 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003523297.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with clinical features of PARS2-related conditions (PMID: 28077841, 29915213, 30237576, 31130284, 32071833, 32514400). It has also been … (more)
This missense change has been observed in individuals with clinical features of PARS2-related conditions (PMID: 28077841, 29915213, 30237576, 31130284, 32071833, 32514400). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 432121). This variant is present in population databases (rs147227819, gnomAD 0.1%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 95 of the PARS2 protein (p.Val95Ile). (less)
|
|
|
Likely pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Developmental and epileptic encephalopathy, 75
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804954.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Apr 26, 2018)
|
no assertion criteria provided
Method: clinical testing
|
PARS2-related disorder
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV000854666.1
First in ClinVar: Dec 09, 2018 Last updated: Dec 09, 2018 |
|
|
|
Pathogenic
(Apr 19, 2023)
|
no assertion criteria provided
Method: literature only
|
DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 75
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000916288.4
First in ClinVar: May 27, 2019 Last updated: Apr 23, 2023 |
Comment on evidence:
In 2 Japanese sisters with developmental and epileptic encephalopathy-75 (DEE75; 618437), Mizuguchi et al. (2017) identified compound heterozygous missense mutations in the PARS2 gene: a … (more)
In 2 Japanese sisters with developmental and epileptic encephalopathy-75 (DEE75; 618437), Mizuguchi et al. (2017) identified compound heterozygous missense mutations in the PARS2 gene: a c.283G-A transition (c.283G-A, NM_155268.3), resulting in a val95-to-ile (V95I) substitution, and a c.607G-A transition, resulting in a glu203-to-lys (E203K; 612036.0006) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The E203K variant was not found in the dbSNP or ExAC databases, whereas the V95I variant was found at a low frequency in both databases (0.00013 in ExAC). Functional studies of the variants and studies of patient cells were not performed. The patients had onset of epileptic spasms at 4 to 5 months of age. In 2 Chinese sisters with DEE75, Yin et al. (2018) identified compound heterozygous mutations in the PARS2 gene: V95I and a 604G-C transversion, resulting in an arg202-to-gly substitution (R202G; 612036.0007) at a conserved residue in the catalytic domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. V95I was found at a low frequency (0.0132%) in ExAC, with a higher frequency (0.161%) among East Asians, with no homozygotes identified; it was also present in the 1000 Genomes Project database (0.000998, 0.005 in East Asians). R202G was not found in the 1000 Genomes Project database, but was found at a low frequency (1.648 x 10(-5)) in the ExAC database. Neither variant was found in the Exome Sequencing Project database. Functional studies of the variants and studies of patient cells were not performed, but each variant was classified as pathogenic according to ACMG guidelines. The patients had onset of seizures at 9 and 3 months of age, respectively. EEG showed hypsarrhythmic and multifocal spikes. In 2 sibs (proband 18DG0406) with DEE75, Maddirevula et al. (2019) identified a homozygous V95I mutation in the PARS2 gene through whole-exome sequencing. The mutation, which was found by exome sequencing of a cohort of over 2,500 patients with various mendelian phenotypes, was present in the heterozygous state in 29 individuals in gnomAD (frequency of 1.047 x 10(-4)), with no homozygotes reported. Functional studies of the variant and studies of patient cells were not performed. (less)
|
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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic testing and counseling: The contribution of next-generation sequencing to epilepsy genetics. | Alsubaie L | Annals of human genetics | 2020 | PMID: 32533790 |
| PARS2-associated mitochondrial disease: A case report of a patient with prolonged survival and literature review. | A Almuqbil M | Molecular genetics and metabolism reports | 2020 | PMID: 32514400 |
| Phenotypes and genotypes of mitochondrial aminoacyl-tRNA synthetase deficiencies from a single neurometabolic clinic. | Al Balushi A | JIMD reports | 2019 | PMID: 32071833 |
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| Autozygome and high throughput confirmation of disease genes candidacy. | Maddirevula S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30237576 |
| The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy. | Yin X | Journal of human genetics | 2018 | PMID: 29915213 |
| PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. | Mizuguchi T | Journal of human genetics | 2017 | PMID: 28077841 |
| Mizuguchi, T., Nakashima, M., Kato, M., Yamada, K., Okanishi, T., Ekhilevitch, N., Mandel, H., Eran, A., Toyono, M., Sawaishi, Y., Motoi, H., Shiina, M., Ogata, K., Miyatake, S., Miyake, N., Saitsu, H., Matsumoto, N. PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. J. Hum. Genet. 62: 525-529, 2017. ::J. Hum. Genet.::62: 525-529, 2017. Note: Erratum: J. Hum. Genet. 62: 587 only, 2017. | - | - | - | - |
Text-mined citations for rs147227819 ...
HelpRecord last updated Sep 29, 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.