Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000823456 | SCV000964316 | likely pathogenic | Frontotemporal dementia | 2023-11-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 336 of the MAPT protein (p.Gln336His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of frontotemporal dementia (PMID: 24081456, 26426266, 34561610, 35020237). ClinVar contains an entry for this variant (Variation ID: 665222). 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 MAPT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 26426266, 33772783). This variant disrupts the p.Gln336 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 15047590, 34561610), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Institute Of Human Genetics Munich, |
RCV000823456 | SCV001150162 | pathogenic | Frontotemporal dementia | 2018-02-01 | criteria provided, single submitter | clinical testing |