Submissions for variant NM_000021.4(PSEN1):c.1254G>C (p.Leu418Phe)

dbSNP: rs63751316

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049005	SCV001213037	pathogenic	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2019-11-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu418 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 29571857), which suggests that this may be a clinically significant amino acid residue. This variant has been reported to affect PSEN1 protein function (PMID: 27930341). This variant has been observed in individual(s) with Alzheimer’s disease (PMID: 16533963, 28350801). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 418 of the PSEN1 protein (p.Leu418Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282436	SCV002572030	likely pathogenic	Alzheimer disease 3	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: PSEN1 c.1254G>C (p.Leu418Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.1254G>C has been reported in the literature in individuals affected with early onset Alzheimer Disease, Type 3 (example, Rogaeva_2001, Leverenz_2006, Lanoiselee_2017). At-least one these cases was sporadic reporting a de-novo origin (Lanoiselee_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Sun_2017). The most pronounced variant effect results in reduced production of both Abeta 42 and Abeta 40 peptides with increased Abeta 42/Abeta 40 ratio relative to the wild-type. The increased molar ratio of Abeta 42 over Abeta 40 is widely used as a surrogate indicator for the pathogenic effect of presenilin and APP mutations. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.