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

gnomAD frequency: 0.00040  dbSNP: rs145039072

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001332597	SCV001524972	uncertain significance	Combined oxidative phosphorylation defect type 21	2020-09-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865759	SCV002113405	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	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.
Breakthrough Genomics, Breakthrough Genomics	RCV001865759	SCV005186886	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV001865759	SCV005396394	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing	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)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001332597	SCV005399011	pathogenic	Combined oxidative phosphorylation defect type 21	2024-10-09	criteria provided, single submitter	clinical testing	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
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV001332597	SCV001738507	likely pathogenic	Combined oxidative phosphorylation defect type 21		no assertion criteria provided	clinical testing
OMIM	RCV001332597	SCV002098048	pathogenic	Combined oxidative phosphorylation defect type 21	2024-04-01	no assertion criteria provided	literature only
Houlden Lab, UCL Institute of Neurology	RCV001332597	SCV003035502	uncertain significance	Combined oxidative phosphorylation defect type 21		no assertion criteria provided	research
Undiagnosed Diseases Network, NIH	RCV001332597	SCV005368720	likely pathogenic	Combined oxidative phosphorylation defect type 21	2024-05-16	no assertion criteria provided	clinical testing