Submissions for variant NM_004614.5(TK2):c.156+2T>C

gnomAD frequency: 0.00003  dbSNP: rs281865499

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520101	SCV000617265	pathogenic	not provided	2017-07-18	criteria provided, single submitter	clinical testing	The c.156+2 T>C splice site variant in the TK2 gene has been previously reported in association with mitochondrial DNA depletion syndrome (Poulton et al., 2009). The c.156+2 T>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant destroys the canonical splice donor site in intron 2, and is expected to cause abnormal gene splicing.
Invitae	RCV000520101	SCV002276189	likely pathogenic	not provided	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the TK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). This variant is present in population databases (rs281865499, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 19748572). This variant is also known as c.282+2T>C. ClinVar contains an entry for this variant (Variation ID: 38977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492321	SCV004241080	likely pathogenic	Mitochondrial DNA depletion syndrome	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: TK2 c.156+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251356 control chromosomes. c.156+2T>C has been reported in the literature in unspecified individual(s) affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (example, Poulton_2009). Detailed individual information was not however provided for an independent analysis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 19748572). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.