Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Kosik Lab, |
RCV001810075 | SCV001751539 | likely pathogenic | Alzheimer disease 3 | 2021-06-01 | criteria provided, single submitter | case-control | ACMG criteria classifies the variant as Pathogenic (PS1, PS4, PM2, PP2, PP3). |
| Athena Diagnostics | RCV002473293 | SCV002771051 | uncertain significance | not provided | 2022-06-03 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002568920 | SCV003212649 | likely pathogenic | Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 | 2022-07-08 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 261 of the PSEN1 protein (p.Val261Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PSEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1178341). 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. This variant disrupts the p.Val261 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 18637955, 24928124), 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. |
| Victorian Clinical Genetics Services, |
RCV004785268 | SCV005400561 | pathogenic | Alzheimer disease | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMID: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Val261Phe), p.(Val261Leu) and p.(Val261Ile) have been observed in multiple unrelated individuals with Alzheimer disease in the literature (PMID: 19021905, 19915487,11524469, 18637955, 34918018, 31920494). p.(Val261Gly) has been classified as benign in ClinVar, however this was not considered to be conflicting evidence of pathogenicity for this amino acid as the glycine substitution is also observed at high frequency in gnomAD, where it fails quality filters. (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and a VUS in ClinVar. This variant has been observed in an individual with Alzheimer disease and classified as likely pathogenic (PMID: 35260199). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |