Submissions for variant NM_004614.5(TK2):c.441del (p.Tyr148fs)

gnomAD frequency: 0.00002  dbSNP: rs768548319

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001785065	SCV002018975	likely pathogenic	not provided	2022-11-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Heidelberg University	RCV003388613	SCV004100314	likely pathogenic	Mitochondrial DNA depletion syndrome, myopathic form	2023-10-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003388613	SCV004101503	likely pathogenic	Mitochondrial DNA depletion syndrome, myopathic form		criteria provided, single submitter	clinical testing	The frameshift deletion p.Y148Ifs*12 in TK2 (NM_004614.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y148Ifs*12 variant has a GnomAD frequency of 0.002387 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 12 residues until a stop codon is reached. The p.Y148Ifs*12 variant is a loss of function variant in the gene TK2, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant was also detected in heterozygous state in the mother.
CeGaT Center for Human Genetics Tuebingen	RCV001785065	SCV004139930	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TK2: PVS1:Strong, PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001785065	SCV004617114	pathogenic	not provided	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr148Ilefs*12) 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 (rs768548319, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323691). For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV004554871	SCV005044143	likely pathogenic	Mitochondrial DNA depletion syndrome, myopathic form; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3	2022-09-22	criteria provided, single submitter	clinical testing	The homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is the deletion of a single nucleotide within exon 6/10 (amino acid 148/266) and is predicted to lead to a frameshift and a premature termination of the protein approximately 12 amino acids downstream. This variant is identified with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8, All of Us), with highest allele frequency of 2.45e-5 (gnomADv2.1.1, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been reported by a clinical lab as Pathogenic in ClinVar (VarID:1323691), however the assertion criteria used for that classification is not available for our review. Other nonsense and frameshift variants downstream of the one identified here have also been reported as Pathogenic or Likely Pathogenic in ClinVar (VarIDs:1327192, 280624, 1414250). While the p.(Tyr148IlefsTer12) variant has not been previously reported in affected individuals in the literature, other nonsense and frameshift variants downstream have been reported in individuals with variable clinical presentations [for review, PMID:29735374, 29602790]. Given its deleterious nature and absence in population databases, the homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is reported here as Likely Pathogenic.
GeneDx	RCV001785065	SCV005079856	pathogenic	not provided	2024-02-15	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; Has not been previously published as pathogenic or benign to our knowledge