14-73192832-C-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV005399926: "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)."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A246A) has been classified as Likely benign.

• 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
• Publications: 383 publications found

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]

PSEN1 Gene-Disease associations (from GenCC):

• Alzheimer disease 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acne inversa, familial, 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1U

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005399926: "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)."; SCV002770445: "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; SCV000639608: 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).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 early-onset autosomal dominant Alzheimer disease, Pick disease, semantic dementia, Alzheimer disease 3, familial isolated dilated cardiomyopathy, dilated cardiomyopathy, dilated cardiomyopathy 1U, acne inversa, familial, 3, 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 VariationId is 18125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000021.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	NM_000021.4	MANE Select	c.737C>A	p.Ala246Glu	missense	Exon 7 of 12	NP_000012.1	A0A024R6A3
	PSEN1	NM_007318.3		c.725C>A	p.Ala242Glu	missense	Exon 7 of 12	NP_015557.2	A0A0S2Z4D2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN1	ENST00000324501.10	TSL:1 MANE Select	c.737C>A	p.Ala246Glu	missense	Exon 7 of 12	ENSP00000326366.5	P49768-1
	PSEN1	ENST00000357710.8	TSL:1	c.725C>A	p.Ala242Glu	missense	Exon 7 of 12	ENSP00000350342.4	P49768-2
	PSEN1	ENST00000394164.5	TSL:1	c.725C>A	p.Ala242Glu	missense	Exon 7 of 12	ENSP00000377719.1	P49768-2

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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111418

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Alzheimer disease 3 (3)
1	-	-	not provided (2)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.77		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750526; hg19: chr14-73659540;