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Table 2 Variants of unknown significance evaluated by the pathogenicity algorithm

From: Discovery and validation of dominantly inherited Alzheimer’s disease mutations in populations from Latin America

PSEN1 variant

Variant location

Variant type/consequence

GnomAD

ClinVar

EVS

SIFT

CADD

Clinical significance according to the ACMG criteria

(Varsome)

Clinical significance according to the ACMG criteria

(Franklin by Genoox)

In vitro analysisa

Clinical significanceb

p.Val103_Ser104delinsGly

c.308_310del

4

chr14:73637725

Deletion, in frame

NP

NA

NA

Pathogenic

Pathogenic

Yes

AD : Pathogenic

p.Lys395Ile

c.1184A>T

11

chr14:73664760

Point, missense

NP

Damaging

31

Pathogenic

Pathogenic

Yes

AD : Pathogenic

p.Pro264Se

c.790C>T

8

chr14:73683888

Point, missense

NP

Damaging

28.4

Pathogenic

Likely pathogenic

Yes

AD : Pathogenic

p.Ala275Thr

c.823G>A

8

chr14:73664792

Point, missense

NP

Damaging

29.4

Likely pathogenic

Likely pathogenic

Yes

AD :

Pathogenic

p. Ile414Thr

c.1241T>C

11

chr14:73683945

Point, missense

NP

Damaging

28.4

Likely pathogenic

Likely pathogenic

No

Not Pathogenic/

Risk factor

  1. GnomAD Genome aggregation database (~17720 Latino origen [12.5%]), EVS Exome Variant Server, dbSNP single nucleotide polymorphisms, SIFT Sorting Intolerant From Tolerant, CADD Combined Annotation Dependent Depletion, NP not present absent as of December 2021
  2. aChange in Aβ consistent with pathogenic mutations
  3. bPathogenicity classification based on the algorithm proposed Hsu et al. [25] PSEN1 transcript ENST00000324501.5; reference genome: hg19