Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189721 | SCV000243369 | uncertain significance | not provided | 2014-06-11 | criteria provided, single submitter | clinical testing | p.Thr170Ala (ACA>GCA): c.508 A>G in exon 8 of the TCF4 gene (NM_001083962.1). The T170A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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 T170A 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. However, in silico analysis predicts the T170A variant likely does not alter the protein structure/function. Additionally, it is not located in a known functional domain, whereas all previously published pathogenic missense mutations have been identified in the functional domains of the TCF4 protein (Whalen et al., 2012). Therefore, based on the currently available information, it is unclear whether the T170A variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Labcorp Genetics |
RCV002514072 | SCV003330274 | uncertain significance | Pitt-Hopkins syndrome | 2023-04-22 | criteria provided, single submitter | clinical testing | 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. 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 TCF4 protein function. ClinVar contains an entry for this variant (Variation ID: 207533). This variant has not been reported in the literature in individuals affected with TCF4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 170 of the TCF4 protein (p.Thr170Ala). |