ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.1225G>A (p.Ala409Thr) (rs63750227)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV000811198 SCV000951452 uncertain significance Alzheimer disease, type 3; Frontotemporal dementia; Pick's disease; Acne inversa, familial, 3 2018-10-23 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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.
VIB Department of Molecular Genetics, University of Antwerp RCV000084406 SCV000116542 not provided not provided no assertion provided not provided

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