Submissions for variant NM_004614.5(TK2):c.604_606del (p.Lys202del)

dbSNP: rs281865501

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498843	SCV000589531	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19265691, 25948719, 12682338, 15571232, 20421844, 31060578, 30634555, 32161153, 31589614, 23230576, 29735374, 34973561)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498843	SCV002203989	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This variant, c.604_606del, results in the deletion of 1 amino acid(s) of the TK2 protein (p.Lys202del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs281865501, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of mitochondrial myopathy (PMID: 12682338, 25948719, 29735374, 31060578). This variant is also known as K244Δ, K171del, and 730_732delAAG. ClinVar contains an entry for this variant (Variation ID: 38995). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265574	SCV002548332	pathogenic	Mitochondrial DNA depletion syndrome	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: TK2 c.604_606delAAG (p.Lys202del) results in an in-frame deletion that is predicted to remove one amino acid from the Deoxynucleoside kinase domain (IPR031314) of the encoded protein. The variant allele was found at a frequency of 4e-06 in 251492 control chromosomes. c.604_606delAAG has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (example, Vila_2003 cited in Villarroya_2009 and Frangini_2009, Camara_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Camara_2015). The most pronounced variant effect results in <10% of normal Thymidine kinase 2 (TK2) enzyme activity in fibroblasts from patients with a homozygous genotype. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000032254	SCV003807157	likely pathogenic	Mitochondrial DNA depletion syndrome, myopathic form	2022-12-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, PM3 strong, PM4, PP1 supporting, PP4
GeneReviews	RCV000032254	SCV000055872	not provided	Mitochondrial DNA depletion syndrome, myopathic form		no assertion provided	literature only