ClinVar Miner

Submissions for variant NM_000447.3(PSEN2):c.1316A>C (p.Asp439Ala)

gnomAD frequency: 0.00004  dbSNP: rs63750110
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172102 SCV000054723 uncertain significance Alzheimer disease 2013-06-24 criteria provided, single submitter research
GeneDx RCV000084269 SCV002008467 uncertain significance not provided 2020-05-26 criteria provided, single submitter clinical testing Previously reported in a male with early onset Alzheimer disease; variant was absent in his unaffected siblings (Lleo et al., 2001); Previously reported as a rare benign variant in an individual with EOAD as well as in multiple control individuals (Sassi et al., 2014); The published functional data demonstrates conflicting evidence of pathogenicity (Walker et al., 2005; Hsu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20375137, 24594196, 25937274, 25104557, 15663477, 11723295, 12925374, 32087291, 19073399, 26836416)
Labcorp Genetics (formerly Invitae), Labcorp RCV000009395 SCV002992246 uncertain significance Alzheimer disease 4 2023-04-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 439 of the PSEN2 protein (p.Asp439Ala). This variant is present in population databases (rs63750110, gnomAD 0.01%). This missense change has been observed in individual(s) with Alzheimer disease and/or Lewy body dementia (PMID: 11723295, 25104557, 26836416). ClinVar contains an entry for this variant (Variation ID: 8847). 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 PSEN2 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PSEN2 function (PMID: 15663477, 32087291). 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.
OMIM RCV000009395 SCV000029613 pathogenic Alzheimer disease 4 2001-11-27 no assertion criteria provided literature only
VIB Department of Molecular Genetics, University of Antwerp RCV000084269 SCV000116405 not provided not provided no assertion provided not provided

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