ClinVar Miner

Submissions for variant NM_004614.5(TK2):c.361C>A (p.His121Asn)

gnomAD frequency: 0.00016  dbSNP: rs137854429
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000013545 SCV000807648 pathogenic Mitochondrial DNA depletion syndrome, myopathic form 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice our laboratory: homozygous in a 4-year-old male with developmental regression, progressive muscle weakness, hypotonia, flat feet, Gower sign, arachnoid cyst; in trans with another pathogenic variant (R183W) in a 16-year-old female with proximal muscle weakness. Heterozygotes are expected to be asymptomatic carriers.
Labcorp Genetics (formerly Invitae), Labcorp RCV001386287 SCV001586464 pathogenic not provided 2021-08-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526595 SCV005039620 pathogenic Mitochondrial DNA depletion syndrome 2024-03-21 criteria provided, single submitter clinical testing Variant summary: TK2 c.361C>A (p.His121Asn) results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250912 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.361C>A has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome (example, Chanprasert_2013, Mancuso_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23932787, 12873860). ClinVar contains an entry for this variant (Variation ID: 12708). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000013545 SCV000033792 pathogenic Mitochondrial DNA depletion syndrome, myopathic form 2012-02-28 no assertion criteria provided literature only

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