Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Very_StrongPM1PM2PP2PP3_StrongPP5
The NM_000021.4(PSEN1):c.275G>C(p.Cys92Ser) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.
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 18 ACMG points.
PS1
Transcript NM_000021.4 (PSEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2028849
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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, 0.953
PP5
Variant 14-73170984-G-C is Pathogenic according to our data. Variant chr14-73170984-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18142.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-73170984-G-C is described in Lovd as [Pathogenic].
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