rs63750886

Positions:

• chr14-73198072-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000021.4(PSEN1):​c.811C>G​(p.Leu271Val) variant causes a missense change involving the alteration of a non-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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 1.73

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical (size 23) in uniprot entity PSN1_HUMAN there are 26 pathogenic changes around while only 0 benign (100%) in NM_000021.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PSEN1. . Gene score misZ: 2.1558 (greater than the threshold 3.09). Trascript score misZ: 3.0986 (greater than threshold 3.09). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. GenCC has associacion of the gene with 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, 0.972
• PP5: Variant 14-73198072-C-G is Pathogenic according to our data. Variant chr14-73198072-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 18148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73198072-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.811C>G	p.Leu271Val	missense_variant	8/12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.811C>G	p.Leu271Val	missense_variant	8/12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease, familial, 3, with unusual plaques Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 28, 2003

- -

Spastic paraparesis;C1843013:Alzheimer disease 3 Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2019

This sequence change replaces leucine with valine at codon 271 of the PSEN1 protein (p.Leu271Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Alzheimer's disease in a family (PMID: 12493737). ClinVar contains an entry for this variant (Variation ID: 18148). This variant has been reported to affect PSEN1 protein function (PMID: 12493737, 27930341). For these reasons, this variant has been classified as Pathogenic. -

Alzheimer disease 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PSEN1 related disorder (ClinVar ID: VCV000018148, PMID:12493737). The variant was co-segregated with Alzheimer disease, type 3, with spastic paraparesis and unusual plaques in multiple affected family members (PMID: 12493737). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12493737). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94>=0.6, 3CNET: 0.883>=0.75). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;.;H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99	D;D;D;.;.
Vest4		0.96
MutPred		0.82		.;Gain of catalytic residue at M270 (P = 0.0036);.;Gain of catalytic residue at M270 (P = 0.0036);.;
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63750886; hg19: chr14-73664780;