Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000183970 | SCV000236463 | uncertain significance | not provided | 2014-10-08 | criteria provided, single submitter | clinical testing | The I617F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I617F variant was not observed in approximately 6,500 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 I617F 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 class conserved in most mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). |
Ambry Genetics | RCV004020240 | SCV000735826 | uncertain significance | not specified | 2023-11-29 | criteria provided, single submitter | clinical testing | The p.I617F variant (also known as c.1849A>T), located in coding exon 4 of the TMPO gene, results from an A to T substitution at nucleotide position 1849. The isoleucine at codon 617 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV001202094 | SCV001373194 | uncertain significance | Loeys-Dietz syndrome 2 | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 617 of the TMPO protein (p.Ile617Phe). This variant is present in population databases (rs759832690, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 202142). 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 not expected to disrupt TMPO protein function with a negative predictive value of 80%. 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. |