Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489241 | SCV000577757 | likely pathogenic | not provided | 2015-05-27 | criteria provided, single submitter | clinical testing | The A173T variant in the PNPT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The A173T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A173T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The A173T variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded |
| Invitae | RCV000489241 | SCV002207975 | uncertain significance | not provided | 2022-07-06 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 173 of the PNPT1 protein (p.Ala173Thr). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs774425075, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with PNPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 427125). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Center for Genomic Medicine, |
RCV003989539 | SCV004807234 | uncertain significance | Combined oxidative phosphorylation defect type 13 | 2024-03-26 | criteria provided, single submitter | clinical testing |