Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000497360 | SCV000589803 | likely pathogenic | not provided | 2016-04-21 | criteria provided, single submitter | clinical testing | The F395L variant has been previously reported as homozygous in three siblings with multisytemic failure and early death; unaffected siblings and parents were heterozygous for the variant (Prasad et al., 2012). The F395L 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 F395L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R391H and R400C ) have been reported in the Human Gene Mutation Database in association with Perrault syndrome with neurological features and complex I deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV000497360 | SCV005835924 | uncertain significance | not provided | 2024-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 395 of the TWNK protein (p.Phe395Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive TWNK-related conditions (PMID: 23375728). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432118). Invitae Evidence 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 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 TWNK protein function. 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. |