Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV000004881 | SCV002059203 | likely pathogenic | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TWNK related disorder (ClinVar ID: VCV000004618, PMID:11431692, PS1_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.806, 3CNET: 0.904, PP3_P). A missense variant is a common mechanism associated with Progressive external ophthalmoplegia with mitochondrial DNA deletions (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Suma Genomics | RCV000004881 | SCV002097013 | pathogenic | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV002512779 | SCV003439656 | pathogenic | not provided | 2023-12-10 | 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 359 of the TWNK protein (p.Ala359Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant progressive external ophthalmoplegia (PMID: 11431692, 24076137). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4618). 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) performed at Invitae indicates that this missense variant is expected to disrupt TWNK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TWNK function (PMID: 20659899). This variant disrupts the p.Ala359 amino acid residue in TWNK. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000004881 | SCV000025057 | pathogenic | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | 2010-09-24 | no assertion criteria provided | literature only | |
| Wellcome Centre for Mitochondrial Research, |
RCV000508874 | SCV000575928 | pathogenic | Mitochondrial disease | 2017-04-07 | no assertion criteria provided | clinical testing |