ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.626G>A (p.Gly209Glu) (rs63750053)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000821428 SCV000962183 likely pathogenic Alzheimer disease, type 3; Frontotemporal dementia; Pick's disease; Acne inversa, familial, 3 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 209 of the PSEN1 protein (p.Gly209Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Alzheimer's disease (PMID: 30045758, 11524469, Invitae). 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.Gly209 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9521418, 9521423, 10468510, 24773620), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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