Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000021.4(PSEN1):c.254T>C(p.Leu85Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L85L) has been classified as Likely benign.
PSEN1 (HGNC:9508): (presenilin 1) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000021.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, PSEN1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
Variant 14-73170963-T-C is Pathogenic according to our data. Variant chr14-73170963-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18153.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73170963-T-C is described in Lovd as [Pathogenic].
.;.;.;Gain of catalytic residue at V89 (P = 0);.;.;Gain of catalytic residue at V89 (P = 0);.;Gain of catalytic residue at V89 (P = 0);.;Gain of catalytic residue at V89 (P = 0);Gain of catalytic residue at V89 (P = 0);.;Gain of catalytic residue at V89 (P = 0);