NM_025150.5(TARS2):c.773C>T (p.Ser258Leu) AND Combined oxidative phosphorylation defect type 21

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Oct 9, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001332597.9

Allele description [Variation Report for NM_025150.5(TARS2):c.773C>T (p.Ser258Leu)]

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

Gene:

TARS2:threonyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.2

Genomic location:

Preferred name:

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

Other names:

p.Ser258Leu

HGVS:

NC_000001.11:g.150492488C>T
NG_034226.1:g.10125C>T
NM_001271895.2:c.773C>T
NM_001271896.2:c.630+977C>T
NM_025150.5:c.773C>TMANE SELECT
NP_001258824.1:p.Ser258Leu
NP_079426.2:p.Ser258Leu
NC_000001.10:g.150464964C>T
NM_025150.4:c.773C>T
NR_073513.2:n.450C>T
NR_073514.2:n.680C>T

Protein change:

S258L; SER258LEU

Links:

OMIM: 612805.0007; dbSNP: rs145039072

NCBI 1000 Genomes Browser:

rs145039072

Molecular consequence:

NM_001271896.2:c.630+977C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001271895.2:c.773C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_025150.5:c.773C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_073513.2:n.450C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_073514.2:n.680C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Combined oxidative phosphorylation defect type 21
Synonyms:: Combined oxidative phosphorylation deficiency 21
Identifiers:: MONDO: MONDO:0014398; MedGen: C4706316; Orphanet: 420733; OMIM: 615918

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001524972	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 9, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001738507	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	no assertion criteria provided	Likely pathogenic	inherited	clinical testing
SCV002098048	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2024)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003035502	Houlden Lab, UCL Institute of Neurology	no assertion criteria provided	Uncertain significance	germline	research
SCV005368720	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	no assertion criteria provided	Likely pathogenic (May 16, 2024)	maternal	clinical testing
SCV005399011	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34508595, 37454282, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.

Zheng WQ, Pedersen SV, Thompson K, Bellacchio E, French CE, Munro B, Pearson TS, Vogt J, Diodato D, Diemer T, Ernst A, Horvath R, Chitre M, Ek J, Wibrand F, Grange DK, Raymond L, Zhou XL, Taylor RW, Ostergaard E.

Hum Mol Genet. 2022 Feb 21;31(4):523-534. doi: 10.1093/hmg/ddab257.

PubMed [citation]

PMID:: 34508595

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.

Accogli A, Lin SJ, Severino M, Kim SH, Huang K, Rocca C, Landsverk M, Zaki MS, Al-Maawali A, Srinivasan VM, Al-Thihli K, Schaefer GB, Davis M, Tonduti D, Doneda C, Marten LM, Mühlhausen C, Gomez M, Lamantea E, Mena R, Nizon M, Procaccio V, et al.

Genet Med. 2023 Nov;25(11):100938. doi: 10.1016/j.gim.2023.100938. Epub 2023 Jul 13.

PubMed [citation]

PMID:: 37454282
PMCID:: PMC11157694

See all PubMed Citations (3)

Details of each submission

From Baylor Genetics, SCV001524972.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV001738507.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV002098048.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Houlden Lab, UCL Institute of Neurology, SCV003035502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV005368720.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	Blood	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005399011.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

ClinVar

Relating variation to medicine