Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000021.4(PSEN1):c.338T>C(p.Leu113Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L113Q) has been classified as 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 19 ACMG points.
PM1
In a topological_domain Lumenal (size 28) in uniprot entity PSN1_HUMAN there are 21 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 chr14-73171047-T-A is described in Lovd as [Pathogenic].
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, 0.977
PP5
Variant 14-73171047-T-C is Pathogenic according to our data. Variant chr14-73171047-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73171047-T-C is described in Lovd as [Pathogenic].
VIB Department of Molecular Genetics, University of Antwerp
Significance: not provided
Review Status: no classification provided
Collection Method: literature only
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Apr 04, 2019
Athena Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Not found in the total gnomAD dataset, and the data is high quality (0/282660 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu113 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 15776278), which suggests that this may be a clinically significant amino acid residue. This variant has been reported not to substantially affect PSEN1 protein function (PMID: 17431506, 20634584). This variant has been observed in an individual and a family affected with clinical features of early-onset Alzheimer's disease (PMID: 11094121, Invitae). This gene is also known as PS1 in the literature. ClinVar contains an entry for this variant (Variation ID: 18145). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 113 of the PSEN1 protein (p.Leu113Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -
.;.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;Gain of catalytic residue at I114 (P = 0.0026);.;