Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000084381 | SCV001501514 | pathogenic | not provided | 2023-01-01 | criteria provided, single submitter | clinical testing | PSEN1: PM1, PM2, PM5, PP1:Moderate, PS4:Moderate, PP4, PS3:Supporting |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000019760 | SCV002600865 | pathogenic | Alzheimer disease 3 | 2022-10-04 | criteria provided, single submitter | clinical testing | Variant summary: PSEN1 c.839A>G (p.Glu280Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250478 control chromosomes. c.839A>G has been reported in the literature in multiple individuals affected with early onset/autosomal dominant familial Alzheimer's disease (Alzheimer Disease, Type 3) (example, Hutton_1996, Ryan_2016, Arber_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Sun_2017). 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV002513125 | SCV003442732 | pathogenic | Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 | 2022-08-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu280 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550356, 22461631, 22766738, 24217025, 25471389, 27930341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 27930341). 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. ClinVar contains an entry for this variant (Variation ID: 18132). This missense change has been observed in individuals with PSEN1-related conditions (PMID: 7550356, 12370477, 16033913, 27777022). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 280 of the PSEN1 protein (p.Glu280Gly). |
| OMIM | RCV000019760 | SCV000040058 | pathogenic | Alzheimer disease 3 | 2003-10-14 | no assertion criteria provided | literature only | |
| OMIM | RCV000019761 | SCV000040059 | pathogenic | Alzheimer disease, familial, with spastic paraparesis and unusual plaques | 2003-10-14 | no assertion criteria provided | literature only | |
| VIB Department of Molecular Genetics, |
RCV000084381 | SCV000116517 | not provided | not provided | no assertion provided | not provided |