rs63750231
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000021.4(PSEN1):c.839A>C(p.Glu280Ala) 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. E280G) has been classified as Pathogenic.
Frequency
Consequence
NM_000021.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.839A>C | p.Glu280Ala | missense_variant | 8/12 | ENST00000324501.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN1 | ENST00000324501.10 | c.839A>C | p.Glu280Ala | missense_variant | 8/12 | 1 | NM_000021.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Alzheimer disease 3 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 13, 2015 | - - |
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 22461631, 24217025, 27930341). 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 expected to disrupt PSEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 18131). This missense change has been observed in individual(s) with early-onset Alzheimer disease (PMID: 7550356, 22766738, 25471389). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 280 of the PSEN1 protein (p.Glu280Ala). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at