VCV000632566.25 - ClinVar

NM_152268.4(PARS2):c.1091C>G (p.Pro364Arg)

Germline

Classification

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)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(4); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_152268.4(PARS2):c.1091C>G (p.Pro364Arg)

Variation ID: 632566 Accession: VCV000632566.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p32.3 1: 54758071 (GRCh38) [ NCBI UCSC ] 1: 55223744 (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	May 27, 2019	Nov 24, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152268.4:c.1091C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689481.2:p.Pro364Arg	missense
NC_000001.11:g.54758071G>C
NC_000001.10:g.55223744G>C
NG_042048.1:g.11483C>G

Protein change

P364R

Other names

p.Pro364Arg

Canonical SPDI

NC_000001.11:54758070:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00100

Exome Aggregation Consortium (ExAC) 0.00106

The Genome Aggregation Database (gnomAD), exomes 0.00106

The Genome Aggregation Database (gnomAD) 0.00128

Trans-Omics for Precision Medicine (TOPMed) 0.00149

Links

OMIM: 612036.0003 dbSNP: rs35201073 VarSome

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
Gene	OMIM	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.
Developmental and epileptic encephalopathy, 75	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	May 8, 2023	RCV000779606.14
not specified	Uncertain significance (1)	criteria provided, single submitter	Oct 14, 2021	RCV001779077.1
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 1, 2024	RCV001548335.13
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Nov 8, 2021	RCV002535659.2

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.
Uncertain significance (Apr 19, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001768229.1 First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021	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: 27290639, … (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: 27290639, 33339579, 32514400, 32071833, 31487502, 29915213, 29410512) (less)
Uncertain significance (Oct 14, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002014911.1 First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021	Publications: PubMed (8) PubMed: 27290639‚ 32514400‚ 32071833‚ 29410512‚ 31487502‚ 27348859‚ 30237576‚ 29915213 Comment: Variant summary: PARS2 c.1091C>G (p.Pro364Arg) results in a non-conservative amino acid change located in the Prokaryote proline-tRNA ligase core domain (IPR033730) of the encoded protein … (more) Variant summary: PARS2 c.1091C>G (p.Pro364Arg) results in a non-conservative amino acid change located in the Prokaryote proline-tRNA ligase core domain (IPR033730) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250554 control chromosomes (gnomAD). c.1091C>G has been reported in the literature in individuals with congenital microcephaly, early infantile epileptic encephalopathy, dilated cardiomyopathy, renal dysfunction and Leigh syndrome-like disease (Pronicka_2016, Yin_2018, Ciara_2018, Costain_2019, Al Balushi_2019, A Almuqbil_2020). These reports do not provide unequivocal conclusions about association of the variant with Developmental And Epileptic Encephalopathy 75. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional clinical and functional evidence become available. (less)
Likely pathogenic (Jan 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 75 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020229.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 12, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002109526.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 27290639‚ 29410512‚ 32071833‚ 32514400 Comment: This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 364 of the PARS2 protein (p.Pro364Arg). … (more) This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 364 of the PARS2 protein (p.Pro364Arg). This variant is present in population databases (rs35201073, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 27290639, 29410512, 32071833, 32514400). 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: 632566). 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)
Uncertain significance (Oct 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Developmental and epileptic encephalopathy, 75 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001146823.1 First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020	Publications: PubMed (1) PubMed: 29410512 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: PP1-Moderate, … (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: PP1-Moderate, PP3. (less)
Likely pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002557609.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 27290639‚ 29410512‚ 32071833‚ 32514400 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a likely … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (295 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been recently reported as a VUS (ClinVar), but also as pathogenic and likely pathogenic, and observed in at least four unrelated compound heterozygous individuals with mitochondrial disease or PARS2 deficiency (LOVD, PMID: 32514400, PMID: 29410512, PMID: 27290639, PMID: 32071833). (I) 0903 - This variant has limited evidence for segregation with disease. It was observed in three affected siblings with mitochondrial disease (PMID: 29410512). (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 (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 75 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004040986.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Uncertain significance (Nov 08, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003587620.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 27290639‚ 32071833‚ 32514400 Comment: The c.1091C>G (p.P364R) alteration is located in exon 2 (coding exon 1) of the PARS2 gene. This alteration results from a C to G substitution … (more) The c.1091C>G (p.P364R) alteration is located in exon 2 (coding exon 1) of the PARS2 gene. This alteration results from a C to G substitution at nucleotide position 1091, causing the proline (P) at amino acid position 364 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Likely pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005050708.5 First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024	Comment: PARS2: PM3:Strong, PP1:Moderate, PM2:Supporting Number of individuals with the variant: 2
Likely pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413651.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (10) PubMed: 27290639‚ 29410512‚ 29915213‚ 31487502‚ 32071833‚ 32514400‚ 33339579‚ 34484863‚ 37956963‚ 38087948 Comment: PP1, PP3, PM3_supporting, PS4 Number of individuals with the variant: 2
Pathogenic (Nov 25, 2020)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 75 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000916285.3 First in ClinVar: May 27, 2019 Last updated: Nov 28, 2020	Publications: PubMed (2) PubMed: 27290639‚ 29410512 Comment on evidence: In 3 Polish sibs with developmental and epileptic encephalopathy-75 (DEE75; 618437), Pronicka et al. (2016) and Ciara et al. (2018) identified compound heterozygous missense mutations … (more) In 3 Polish sibs with developmental and epileptic encephalopathy-75 (DEE75; 618437), Pronicka et al. (2016) and Ciara et al. (2018) identified compound heterozygous missense mutations in the PARS2 gene: a c.1091C-G transversion (c.1091C-G, NM_152268.3), resulting in a pro364-to-arg (P364R) substitution, and a c.239T-C transition, resulting in an ile80-to-thr substitution (I80T; 612036.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The P364R variant was found at a low frequency in the 1000 Genomes Project database (0.0014), whereas the I80T variant was not present in that database. The patients were initially ascertained from a cohort of 113 Polish patients with suspected mitochondrial disorders who underwent whole-exome sequencing (Pronicka et al., 2016). Functional studies of the variants and studies of patient cells were not performed. Ciara et al. (2018) provided follow-up of this family, noting that molecular modeling predicted that the P364R mutation is located at a highly conserved residue on the loop that joins the catalytic and anticodon binding domains, and the I80T mutation is located at a moderately conserved residue in a region that stabilizes the conformation of the protein and may affect homodimerization. Ciara et al. (2018) stated that only the I80T variant was found at low frequencies in the ExAC (0.001041) and Exome Sequencing Project (0.0014) databases. Functional studies of the variants were not performed. The patients had onset of infantile spasms and myoclonic seizures between 4 and 5 months of age. EEG showed hypsarrhythmia, consistent with a clinical diagnosis of West syndrome. Two of the patients died in childhood. (less)
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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: 27290639, 33339579, 32514400, 32071833, 31487502, 29915213, 29410512)

Comment:

Variant summary: PARS2 c.1091C>G (p.Pro364Arg) results in a non-conservative amino acid change located in the Prokaryote proline-tRNA ligase core domain (IPR033730) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 250554 control chromosomes (gnomAD). c.1091C>G has been reported in the literature in individuals with congenital microcephaly, early infantile epileptic encephalopathy, dilated cardiomyopathy, renal dysfunction and Leigh syndrome-like disease (Pronicka_2016, Yin_2018, Ciara_2018, Costain_2019, Al Balushi_2019, A Almuqbil_2020). These reports do not provide unequivocal conclusions about association of the variant with Developmental And Epileptic Encephalopathy 75. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional clinical and functional evidence become available.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 364 of the PARS2 protein (p.Pro364Arg). This variant is present in population databases (rs35201073, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 27290639, 29410512, 32071833, 32514400). 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: 632566). 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (295 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been recently reported as a VUS (ClinVar), but also as pathogenic and likely pathogenic, and observed in at least four unrelated compound heterozygous individuals with mitochondrial disease or PARS2 deficiency (LOVD, PMID: 32514400, PMID: 29410512, PMID: 27290639, PMID: 32071833). (I) 0903 - This variant has limited evidence for segregation with disease. It was observed in three affected siblings with mitochondrial disease (PMID: 29410512). (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

Comment:

The c.1091C>G (p.P364R) alteration is located in exon 2 (coding exon 1) of the PARS2 gene. This alteration results from a C to G substitution at nucleotide position 1091, causing the proline (P) at amino acid position 364 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike-and-wave activation in sleep.	Licchetta L	Molecular genetics & genomic medicine	2024	PMID: 38087948
Novel mutation in PARS2 revealed highly variable phenotype of developmental and epileptic encephalopathy-75.	Hu X	Gene	2024	PMID: 37956963
The regulatory roles of aminoacyl-tRNA synthetase in cardiovascular disease.	Zou Y	Molecular therapy. Nucleic acids	2021	PMID: 34484863
Genetic aspects of the oxidative phosphorylation dysfunction in dilated cardiomyopathy.	Bayona-Bafaluy MP	Mutation research. Reviews in mutation research	2020	PMID: 33339579
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
Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy.	Costain G	Neuroscience	2019	PMID: 31487502
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
Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations.	Ciara E	Journal of human genetics	2018	PMID: 29410512
Chronic Rhinosinusitis Patients Show Accumulation of Genetic Variants in PARS2.	Henmyr V	PloS one	2016	PMID: 27348859
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.	Pronicka E	Journal of translational medicine	2016	PMID: 27290639
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Text-mined citations for rs35201073 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_152268.4(PARS2):c.1091C>G (p.Pro364Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35201073 ...