VCV001030907.39 - ClinVar

NM_025150.5(TARS2):c.773C>T (p.Ser258Leu)

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.

(9)

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(1); 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_025150.5(TARS2):c.773C>T (p.Ser258Leu)

Variation ID: 1030907 Accession: VCV001030907.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.2 1: 150492488 (GRCh38) [ NCBI UCSC ] 1: 150464964 (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	Mar 22, 2021	Nov 24, 2024	Nov 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025150.5:c.773C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079426.2:p.Ser258Leu	missense
NM_001271895.2:c.773C>T	NP_001258824.1:p.Ser258Leu	missense
NM_001271896.2:c.630+977C>T		intron variant
NR_073513.2:n.450C>T		non-coding transcript variant
NR_073514.2:n.680C>T		non-coding transcript variant
NC_000001.11:g.150492488C>T
NC_000001.10:g.150464964C>T
NG_034226.1:g.10125C>T

... more HGVS ... less HGVS

Protein change

S258L

Other names

p.Ser258Leu

Canonical SPDI

NC_000001.11:150492487:C:T

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.

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD), exomes 0.00035

The Genome Aggregation Database (gnomAD) 0.00042

Trans-Omics for Precision Medicine (TOPMed) 0.00054

Links

OMIM: 612805.0007 dbSNP: rs145039072 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.
TARS2		-	-	GRCh38 GRCh37	260	278

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.
Combined oxidative phosphorylation defect type 21	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Oct 9, 2024	RCV001332597.9
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 11, 2024	RCV001865759.10

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 (Sep 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 21 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524972.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Dec 07, 2023)	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: SCV002113405.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 34508595 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 258 of the TARS2 protein (p.Ser258Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 258 of the TARS2 protein (p.Ser258Leu). This variant is present in population databases (rs145039072, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive mitochondrial encephalomypathy (PMID: 34508595). ClinVar contains an entry for this variant (Variation ID: 1030907). 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 tolerated. Experimental studies have shown that this missense change affects TARS2 function (PMID: 34508595). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005186886.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Nov 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005396394.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Comment: Published functional studies suggest a damaging effect as aminoacylation assays showed decreased activity compared with wild type (PMID: 34508595); In silico analysis indicates that this … (more) Published functional studies suggest a damaging effect as aminoacylation assays showed decreased activity compared with wild type (PMID: 34508595); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37669377, 36218002, 34508595, 35586607, 37454282) (less)
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined oxidative phosphorylation defect type 21 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399011.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 34508595‚ 37454282 Comment: Updated: 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 known … (more) Updated: 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 known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 21 (MIM#615918). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 98 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tRNA_SAD domain (DECIPHER). (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 observed in both compound heterozygous and homozygous individuals with TARS2-related features (PMIDs: 34508595, 37454282). This variant has also been classified as VUS and likely pathogenic in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. p.(Ser258Leu) had decreased amino acid activation, aminoacylation and steady state level, as well as increased binding affinity compared to WT (PMID: 34508595). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Combined oxidative phosphorylation defect type 21 Affected status: yes Allele origin: inherited	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV001738507.2 First in ClinVar: Jun 25, 2021 Last updated: Sep 03, 2023
Uncertain significance (-)	no assertion criteria provided Method: research	Combined oxidative phosphorylation defect type 21 Affected status: yes Allele origin: germline	Houlden Lab, UCL Institute of Neurology Accession: SCV003035502.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 Comment: This variant was identified in a compound heterozygous state with another TARS2 variant (c.1534G>A) for this condition.
Pathogenic (Apr 01, 2024)	no assertion criteria provided Method: literature only	COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 21 Affected status: not provided Allele origin: germline	OMIM Accession: SCV002098048.2 First in ClinVar: Feb 26, 2022 Last updated: Apr 06, 2024	Publications: PubMed (1) PubMed: 34508595 Comment on evidence: In an Indian patient (patient 3) with combined oxidative phosphorylation deficiency-21 (COXPD21; 615918), Zheng et al. (2022) identified compound heterozygous mutations in the TARS2 gene: … (more) In an Indian patient (patient 3) with combined oxidative phosphorylation deficiency-21 (COXPD21; 615918), Zheng et al. (2022) identified compound heterozygous mutations in the TARS2 gene: a c.773C-T transition (c.773C-T, NM_025150.4), resulting in a ser258-to-leu (S258L) substitution, and a c.1838C-T transition, resulting in a pro613-to-leu (P613L; 612085.0008) substitution at a highly conserved residue. The mutations were identified by whole-exome or whole-genome sequencing. The S258L mutation was present in the gnomAD database at an allele frequency of 98/282822, and the P613L mutation was present in the gnomAD database at an allele frequency of 3/251422. TARS2 protein expression was decreased in patient fibroblasts. TARS2 with the S258L mutation was shown to have increased tRNA binding affinity, decreased amino acid activation activity, and decreased aminoacylation activity. (less)
Likely pathogenic (May 16, 2024)	no assertion criteria provided Method: clinical testing	Combined oxidative phosphorylation defect type 21 Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV005368720.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Number of individuals with the variant: 1 Clinical Features: Primary amenorrhea (present) , Premature ovarian insufficiency (present) , Speech apraxia (present) , Cognitive impairment (present) Zygosity: Compound Heterozygote Age: 20-29 years Sex: female Tissue: Blood

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 258 of the TARS2 protein (p.Ser258Leu). This variant is present in population databases (rs145039072, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive mitochondrial encephalomypathy (PMID: 34508595). ClinVar contains an entry for this variant (Variation ID: 1030907). 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 tolerated. Experimental studies have shown that this missense change affects TARS2 function (PMID: 34508595). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Published functional studies suggest a damaging effect as aminoacylation assays showed decreased activity compared with wild type (PMID: 34508595); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37669377, 36218002, 34508595, 35586607, 37454282)

Comment:

Updated: 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 known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 21 (MIM#615918). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 98 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tRNA_SAD domain (DECIPHER). (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 observed in both compound heterozygous and homozygous individuals with TARS2-related features (PMIDs: 34508595, 37454282). This variant has also been classified as VUS and likely pathogenic in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. p.(Ser258Leu) had decreased amino acid activation, aminoacylation and steady state level, as well as increased binding affinity compared to WT (PMID: 34508595). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.	Accogli A	Genetics in medicine : official journal of the American College of Medical Genetics	2023	PMID: 37454282
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.	Zheng WQ	Human molecular genetics	2022	PMID: 34508595

Text-mined citations for rs145039072 ...

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 30, 2024

ClinVar Genomic variation as it relates to human health

NM_025150.5(TARS2):c.773C>T (p.Ser258Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145039072 ...