Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000084406 | SCV000577154 | likely pathogenic | not provided | 2017-04-10 | criteria provided, single submitter | clinical testing | The A409T variant in the PSEN1 gene has been reported previously as heterozygous in an individual with onset of Alzheimer disease at age 58 years and no family history (Aldudo et al., 1999). The A409T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A409T 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N405S, I408T, C410Y, V412I) have been reported in the Human Gene Mutation Database in association with PSEN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret A409T as a likely pathogenic variant. |
| Labcorp Genetics |
RCV000811198 | SCV000951452 | uncertain significance | Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3 | 2018-10-16 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change results in decreased Aβ40 and Aβ42 peptide production compared to wild-type (PMID: 27930341). 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. This variant has been observed in an individual affected with early onset Alzheimer disease (PMID: 10533070). ClinVar contains an entry for this variant (Variation ID: 98109). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 409 of the PSEN1 protein (p.Ala409Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004767067 | SCV005380720 | likely pathogenic | Alzheimer disease 3 | 2024-08-09 | criteria provided, single submitter | clinical testing | Variant summary: PSEN1 c.1225G>A (p.Ala409Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251460 control chromosomes. c.1225G>A has been reported in the literature in at least two individuals affected with Alzheimer Disease, Type 3 (Aldudo_1999, Nicolas_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in significant reduction in A42 and A40 production and A42/A40 ratios (Sun_2016). The following publications have been ascertained in the context of this evaluation (PMID: 10533070, 38281098, 28985224, 27930341). ClinVar contains an entry for this variant (Variation ID: 98109). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| VIB Department of Molecular Genetics, |
RCV000084406 | SCV000116542 | not provided | not provided | no assertion provided | not provided |