rs63750526

Variant names:

• chr14-73192832-C-A
• rs63750526
• NM_000021.4:c.737C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-73192832-C-A
• chr14-73192832-C-T

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.737C>A​(p.Ala246Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 4.84

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 helix (size 19) in uniprot entity PSN1_HUMAN there are 19 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 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, 0.948
• PP5: Variant 14-73192832-C-A is Pathogenic according to our data. Variant chr14-73192832-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73192832-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.737C>A	p.Ala246Glu	missense_variant	Exon 7 of 12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.737C>A	p.Ala246Glu	missense_variant	Exon 7 of 12	1	NM_000021.4	ENSP00000326366.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease 3 Pathogenic:3

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMIDs: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by two clinical laboratories (ClinVar) and has been reported in multiple individuals affected with familial Alzheimer disease (PMIDs: 7596406, 35847683, 33413468). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to elevate lysosomal pH in human fibroblasts, resulting in reduced protein autophagy and upregulated explression of genes and proteins linked to lysosomal pH (PMID: 24418614). In addition, transgenic mice models have shown elevated concentrations of A-beta protein in the absence of plaque formation, resulting in disinhibition, psychomotor slowing, and loss of motor skills (PMID: 12493631). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 29, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:1 Other:1

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 29, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341). -

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

Sep 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		0.98	D;D;D;.;.
Vest4		0.94
MutPred		0.77		.;Gain of catalytic residue at E243 (P = 0.0483);.;Gain of catalytic residue at E243 (P = 0.0483);.;
MVP		0.99
MPC		1.5
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.99

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: rs63750526; hg19: chr14-73659540;