Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000021.4(PSEN1):c.358G>A(p.Glu120Lys) 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 Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E120D) 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 15 ACMG points.
PS1
?
PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Transcript NM_000021.4 (PSEN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000021.4
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr14-73173587-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 18135.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, PSEN1
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.941
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-73173585-G-A is Pathogenic according to our data. Variant chr14-73173585-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98019.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73173585-G-A is described in Lovd as [Pathogenic].
.;.;Gain of methylation at E120 (P = 0.0062);.;Gain of methylation at E120 (P = 0.0062);Gain of methylation at E120 (P = 0.0062);.;Gain of methylation at E120 (P = 0.0062);.;