Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001581548 | SCV001813260 | likely pathogenic | not provided | 2020-12-16 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18575922, 12707443, 19428252, 23719791, 19353676, 20479361, 24091712, 22353293, 20880070, 27551684, 20659899) |
| Revvity Omics, |
RCV001581548 | SCV003822377 | likely pathogenic | not provided | 2019-06-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001581548 | SCV004295688 | pathogenic | not provided | 2023-06-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg303 amino acid residue in TWNK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19353676, 20479361, 31271879). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1210826). This missense change has been observed in individuals with autsomal dominant progressive external ophthalmoplegia (PMID: 12707443, 19428252). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 303 of the TWNK protein (p.Arg303Trp). |
| Victorian Clinical Genetics Services, |
RCV004785286 | SCV005399988 | pathogenic | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286) (PMID: 18971204). (I) 0108 - This gene is associated with both recessive and dominant disease. Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MIM#271245) and Perrault syndrome 5 (MIM#616138) are inherited in a recessive manner, whereas progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286) is a dominant condition (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated topoisomerase-primase (TORPIM) nucleotidyl transferase/hydrolase domain (NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change to glutamine at the same residue has previously been reported as pathogenic in individuals with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286) (PMID: 20479361). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals and families with autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286) (PMIDs: 18575922, 20479361). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |