Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002517410 | SCV003444460 | likely pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 43 of the TYMP protein (p.Lys43Thr). This variant is present in population databases (rs752137335, gnomAD 0.02%). This missense change has been observed in individual(s) with TYMP-related conditions (PMID: 14720311). ClinVar contains an entry for this variant (Variation ID: 223015). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TYMP protein function. 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, |
RCV003235133 | SCV003934812 | uncertain significance | not specified | 2023-05-30 | criteria provided, single submitter | clinical testing | Variant summary: TYMP c.128A>C (p.Lys43Thr) results in a non-conservative amino acid change located in the N-terminal domain (IPR017459) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.128A>C has been reported in the literature in an individual affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type), who fulfilled the clinical criteria for the disease, and had undetectable thymidine phosphorylase (TP) activity with elevated plasma thymidine levels (Hirano_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a neighboring missense change (p.R44Q) has also been reported in affected individual(s) (HGMD), indicating a functional importance for this protein region. The following publications have been ascertained in the context of this evaluation (PMID: 14720311, 17549623, 19748572). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic / likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Gene |
RCV000208616 | SCV000264497 | pathogenic | Mitochondrial DNA depletion syndrome 1 | 2016-01-14 | no assertion criteria provided | literature only |