14-73192712-G-C

Position:

chr14-73192712-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000021.4(PSEN1):c.617G>C(p.Gly206Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,032 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G206S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PSEN1
NM_000021.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000021.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-73192712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 807473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, PSEN1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

PP5

Variant 14-73192712-G-C is Pathogenic according to our data. Variant chr14-73192712-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73192712-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSEN1	NM_000021.4 linkuse as main transcript	c.617G>C	p.Gly206Ala	missense_variant	7/12	ENST00000324501.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN1	ENST00000324501.10 linkuse as main transcript	c.617G>C	p.Gly206Ala	missense_variant	7/12	1	NM_000021.4	P4	P49768-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000125

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000287

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2023	The PSEN1 c.617G>C; p.Gly206Ala variant (rs63750082) is reported in the literature in several individuals and families affected with early-onset Alzherimer's disease, and is a founder in the Carribean Hispanic population (Athan 2001, Arnold 2013, Lee 2014, Ravenscroft 2016, see link to Alzforum database). This variant is reported in ClinVar (Variation ID: 18143), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 206 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show an impaired ability to properly cleave amyloid precursor protein, which can lead to increased amyloid plaque formation (Athan 2001, Sun 2017). Based on available information, this variant is considered to be pathogenic. References: Link to Alzforum database: https://www.alzforum.org/mutations/psen1-g206a Athan ES et al. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. Arnold SE et al. Frequency and clinicopathological characteristics of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia. J Alzheimers Dis. 2013;33(4):1089-95. Lee JH et al. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Ravenscroft TA et al. The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida. Am J Neurodegener Dis. 2016 Mar 1;5(1):94-101. Sun L et al. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2023	This variant is statistically more frequent in individuals affected with Alzheimer disease (AD) than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is considered a founder variant among individuals of Caribbean Hispanic ancestry (PMID: 11710891, 23114514, 25333068, 27073747). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. This variant occurs as the most likely explanation for disease in a significant number of internal cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in increased amyloid-beta 42 peptide production (PMID: 11710891, 12119298, 27930341, 32032730). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 24, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2022	Published functional studies demonstrate a damaging effect resulting in an increase of the amyloid beta ratio (Pimenova et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22312439, 11710891, 23383383, 22584618, 17522104, 23114514, 25333068, 11524469, 27312774, 27614114, 18797263, 26756738, 23885714, 22475797, 21952501, 20047059, 12119298, 30279455, 27073747, 27930341, 32032730) -

Alzheimer disease 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 14, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2023	Variant summary: PSEN1 c.617G>C (p.Gly206Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251492 control chromosomes. c.617G>C has been reported in the literature in multiple individuals of Caribbean ancestry affected with Alzheimer Disease, Type 3 (Example: Athan_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function indicating an increase in amyloid-beta 42 peptide production (Athan_2001). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publication have been ascertained in the context of this evaluation (PMID: 11710891). All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 206 of the PSEN1 protein (p.Gly206Ala). This variant is present in population databases (rs63750082, gnomAD 0.003%). This missense change has been observed in individual(s) with early and late onset Alzheimer disease and Alzheimer disease (PMID: 11524469, 11710891, 18797263, 22312439, 23114514, 25333068, 27073747). It is commonly reported in individuals of Caribbean ancestry (PMID: 11524469, 11710891, 18797263, 22312439, 23114514, 25333068, 27073747). ClinVar contains an entry for this variant (Variation ID: 18143). 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 not expected to disrupt PSEN1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 11710891, 27930341). For these reasons, this variant has been classified as Pathogenic. -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3;C3160720:Dilated cardiomyopathy 1U

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.7

D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.016

D;D;D;D;D

Sift4G

Uncertain

0.049

D;D;D;T;T

Polyphen

0.99

D;D;D;.;.

Vest4

0.93

MutPred

0.76

.;Gain of catalytic residue at L201 (P = 0);.;Gain of catalytic residue at L201 (P = 0);.;

MVP

0.98

MPC

1.5

ClinPred

0.95

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over