Submissions for variant NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)

dbSNP: rs63750526

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542870	SCV000639608	pathogenic	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2017-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000084361	SCV002770445	pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000019753	SCV005399926	pathogenic	Alzheimer disease 3	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMIDs: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by two clinical laboratories (ClinVar) and has been reported in multiple individuals affected with familial Alzheimer disease (PMIDs: 7596406, 35847683, 33413468). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to elevate lysosomal pH in human fibroblasts, resulting in reduced protein autophagy and upregulated explression of genes and proteins linked to lysosomal pH (PMID: 24418614). In addition, transgenic mice models have shown elevated concentrations of A-beta protein in the absence of plaque formation, resulting in disinhibition, psychomotor slowing, and loss of motor skills (PMID: 12493631). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000019753	SCV000040051	pathogenic	Alzheimer disease 3	1995-06-29	no assertion criteria provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084361	SCV000116497	not provided	not provided		no assertion provided	not provided
Solve-RD Consortium	RCV000019753	SCV005091231	likely pathogenic	Alzheimer disease 3	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team