Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000021.4(PSEN1):c.415A>G(p.Met139Val) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M139I) has been classified as Likely pathogenic.
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 17 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity PSN1_HUMAN there are 30 pathogenic changes around while only 0 benign (100%) in NM_000021.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.933
PP5
Variant 14-73173642-A-G is Pathogenic according to our data. Variant chr14-73173642-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 18128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73173642-A-G is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the PSEN1 protein (p.Met139Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset familial Alzheimer disease (PMID: 7550356). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18128). 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 not expected to disrupt PSEN1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
.;.;Gain of catalytic residue at V142 (P = 0);.;Gain of catalytic residue at V142 (P = 0);Gain of catalytic residue at V142 (P = 0);.;Gain of catalytic residue at V142 (P = 0);.;