NM_025150.5(TARS2):c.773C>T (p.Ser258Leu) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001865759.10

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]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002113405	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34508595, 28492532
SCV005186886	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV005396394	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 11, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002113405

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 7, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005186886

Breakthrough Genomics, Breakthrough Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

not provided

PubMed (1)
[See all records that cite this PMID]

SCV005396394

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 11, 2024)

germline

clinical testing

Citation Link

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, not provided
not provided	germline	unknown	not provided	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002113405.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

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

From Breakthrough Genomics, Breakthrough Genomics, SCV005186886.1

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

#	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 GeneDx, SCV005396394.1

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

Description

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)

#	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

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