chr14-73219177-C-A

Variant names:

• chr14-73219177-C-A
• rs63750083
• NM_000021.4:c.1292C>A
• PSEN1 p.Ala431Glu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_StrongPP5_Strong

The NM_000021.4(PSEN1):c.1292C>A (p.Ala431Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.83). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002500189: "At least two publications report experimental evidence evaluating an impact on protein function demonstrating a modulation of the gamma secretase activity and an increased ratio of long A-beta APP (amyloid precursor protein) cleavage fragments over shorter ones, exemplified by the ratio of A-beta42 over A-beta 40, consistent with the established pathophysiology of disease (example, Portelius_2010, Sun_2017)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.A431V: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 98113) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 NM_000021.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.83
• Publications: 107 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Pick disease

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• familial dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV002500189: "At least two publications report experimental evidence evaluating an impact on protein function demonstrating a modulation of the gamma secretase activity and an increased ratio of long A-beta APP (amyloid precursor protein) cleavage fragments over shorter ones, exemplified by the ratio of A-beta42 over A-beta 40, consistent with the established pathophysiology of disease (example, Portelius_2010, Sun_2017)."; SCV000614819: Assessment of experimental evidence suggests this variant results in abnormal protein function. A study shows this variant results in increased amyloid-beta 42 peptide production (PMID: 27930341).; SCV001811424: Published functional studies demonstrate a damaging effect (Nelson et al., 2010; Sun et al., 2017); SCV002048085: Functional studies indicate this variant inhibits gamma secretase activity and impair its function as a calcium leak channel (Nelson 2010, Sun 2017).; SCV000762200: Experimental studies have shown that this missense change affects PSEN1 function (PMID: 20145736, 20634584, 21373759, 27930341).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 13 pathogenic, 1 benign (OR vs. background: 45.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.A431V: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 98113)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 3.106). ClinVar shows strong pathogenic missense enrichment: 151 P/LP and 12 B/LB missense entries (ratio 12.6×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (11/11 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PSEN1 NM_000021.4	MANE Select	c.1292C>A p.Ala431Glu	missense	Exon 12 of 12	Prot: NP_000012.1 UniProt:
	PSEN1 NM_007318.3		c.1280C>A p.Ala427Glu	missense	Exon 12 of 12	Prot: NP_015557.2 UniProt:

PSEN1 NM_000021.4

MANE Select

HGVSc / HGVSpc.1292C>Ap.Ala431Glu

Exon rankExon 12 of 12

missense

Prot: NP_000012.1UniProt: A0A024R6A3P49768-1

PSEN1 NM_007318.3

HGVSc / HGVSpc.1280C>Ap.Ala427Glu

Exon rankExon 12 of 12

missense

Prot: NP_015557.2UniProt: P49768-2A0A0S2Z4D2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PSEN1 ENST00000324501.10	TSL:1MANE Select	c.1292C>A p.Ala431Glu	missense	Exon 12 of 12	Prot: ENSP00000326366.5 UniProt:
	PSEN1 ENST00000357710.8	TSL:1	c.1280C>A p.Ala427Glu	missense	Exon 12 of 12	Prot: ENSP00000350342.4 UniProt:
	PSEN1 ENST00000394164.5	TSL:1	c.1280C>A p.Ala427Glu	missense	Exon 12 of 12	Prot: ENSP00000377719.1 UniProt:

PSEN1 ENST00000324501.10

TSL:1MANE Select

HGVSc / HGVSpc.1292C>Ap.Ala431Glu

Exon rankExon 12 of 12

missense

Prot: ENSP00000326366.5UniProt: P49768-1

PSEN1 ENST00000357710.8

TSL:1

HGVSc / HGVSpc.1280C>Ap.Ala427Glu

Exon rankExon 12 of 12

missense

Prot: ENSP00000350342.4UniProt: P49768-2

PSEN1 ENST00000394164.5

TSL:1

HGVSc / HGVSpc.1280C>Ap.Ala427Glu

Exon rankExon 12 of 12

missense

Prot: ENSP00000377719.1UniProt: P49768-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:27248	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Alzheimer disease 3 (5)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 (1)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3;C3160720:Dilated cardiomyopathy 1U (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	31
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.7	H
PhyloP100	Pathogenic	7.8
popEVE	Pathogenic	-5.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.92
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs63750083;

hg19: chr14-73685885;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar