ClinVar Miner

Submissions for variant NM_022445.4(TPK1):c.246C>A (p.Tyr82Ter)

gnomAD frequency: 0.00001  dbSNP: rs970696642
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001236931 SCV001409672 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2023-05-16 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 962978). This variant has not been reported in the literature in individuals affected with TPK1-related conditions. This sequence change creates a premature translational stop signal (p.Tyr82*) in the TPK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPK1 are known to be pathogenic (PMID: 22152682, 25458521).
GeneDx RCV001572409 SCV001797040 likely pathogenic not provided 2023-10-16 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Nonsense 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: 25458521, 22152682)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001236931 SCV004813237 pathogenic Childhood encephalopathy due to thiamine pyrophosphokinase deficiency 2024-02-21 criteria provided, single submitter clinical testing Variant summary: TPK1 c.246C>A (p.Tyr82X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.4e-06 in 1606428 control chromosomes (gnomAD). To our knowledge, no occurrence of c.246C>A in individuals affected with Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 962978). Based on the evidence outlined above, the variant was classified as pathogenic.

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