ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.404A>G (p.Asn135Ser) (rs63751278)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000084303 SCV000843417 likely pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing
Invitae RCV000824341 SCV000965236 pathogenic Alzheimer disease, type 3; Frontotemporal dementia; Pick's disease; Acne inversa, familial, 3 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 135 of the PSEN1 protein (p.Asn135Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with early-onset Alzheimer's disease (AD), and was observed to segregate with AD in two families (PMID: 15776278, 18580586, 23383383). ClinVar contains an entry for this variant (Variation ID: 98022). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asn135 amino acid residue in PSEN1. Other variants that disrupt this residue (p.Asn135Asp, p.Asn135Tyr) have been observed in individuals with PSEN1-related conditions (PMID: 9225696, 27793474), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp RCV000084303 SCV000116439 not provided not provided no assertion provided not provided

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