Submissions for variant NM_004614.5(TK2):c.144_145del (p.Lys50fs)

dbSNP: rs1454450104

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University	RCV001249197	SCV001422447	pathogenic	Mitochondrial DNA depletion syndrome, myopathic form	2019-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002570396	SCV003512753	pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys50Ilefs*99) in the TK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of TK2-related conditions (PMID: 29602790, 32348839). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.144_145delTC. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001249197	SCV003841551	pathogenic	Mitochondrial DNA depletion syndrome, myopathic form	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TK2 related disorder (PMID: 29602790). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Pediatrics, Sichuan Provincial Hospital For Women And Children	RCV001249197	SCV005073697	pathogenic	Mitochondrial DNA depletion syndrome, myopathic form		criteria provided, single submitter	provider interpretation	PVS1+PM2_Supporting+PM3_Strong
GeneDx	RCV002570396	SCV005327026	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33013660, 29602790, 32348839)