Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Diagnostics Laboratory, |
RCV001261442 | SCV001438739 | likely pathogenic | Alzheimer disease 3 | 2020-06-12 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001261442 | SCV002571939 | likely pathogenic | Alzheimer disease 3 | 2022-08-11 | criteria provided, single submitter | clinical testing | Variant summary: PSEN1 c.800C>T (p.Pro267Leu) results in a non-conservative amino acid change in the encoded protein sequence. Several mutations associated with very early onset of disease involve a proline residue, suggesting that these mutations may drastically alter the conformation of the presenilin protein by the substitution of hydrophobic and hydrophilic amino acids (as cited in Larner_2006). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250768 control chromosomes. c.800C>T has been reported in the literature in at-least one individual affected with Early onset Alzheimer Disease who continues to be cited by others (example, Larner_2003). At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as primary data are not provided (Ben-Gedalya_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV002514496 | SCV003442317 | likely pathogenic | Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 | 2023-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the PSEN1 protein (p.Pro267Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset Alzheimer disease (PMID: 12817569, 15094846; Invitae). ClinVar contains an entry for this variant (Variation ID: 98081). 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 PSEN1 protein function with a positive predictive value of 80%. This variant disrupts the p.Pro267 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 7550356, 26888304, 27777022), 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. |
| VIB Department of Molecular Genetics, |
RCV000084372 | SCV000116508 | not provided | not provided | no assertion provided | not provided |