Submissions for variant NM_000021.4(PSEN1):c.1156T>G (p.Phe386Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003337771	SCV004048040	uncertain significance	Alzheimer disease 3		criteria provided, single submitter	clinical testing	The missense c.1156T>G (p.Phe386Val) variant in PSEN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Phe at position 386 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe386Val in PSEN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003777435	SCV004610220	uncertain significance	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 386 of the PSEN1 protein (p.Phe386Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Alzheimer disease (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN1 protein function with a positive predictive value of 80%. This variant disrupts the p.Phe386 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 16033913, 24559647, 27816212, 34901437), which suggests that this may be a clinically significant amino acid residue. 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.