ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.104G>A (p.Arg35Gln) (rs63750592)

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Total submissions: 3
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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 RCV000172094 SCV000054832 uncertain significance Alzheimer's disease 2013-06-24 criteria provided, single submitter research
Invitae RCV000640608 SCV000762202 uncertain significance Alzheimer disease, type 3; Frontotemporal dementia; Pick's disease; Acne inversa, familial, 3 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 35 of the PSEN1 protein (p.Arg35Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63750592, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with Alzheimer disease and dementia (PMID: 11524469, 23990795, 26242991) and has also been reported in an unaffected control (PMID: 18667258). ClinVar contains an entry for this variant (Variation ID: 98004). Experimental studies have shown that this missense change reduces the secretase activity of the PSEN1 protein, but does not produce a significantly higher ratio of long amyloid precursor proteins (AB42) which is typically associated with Alzheimer disease (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 RCV000084280 SCV000116416 not provided not provided no assertion provided not provided

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