Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010373 A>G
Position: (GRCh37/hg19):Chr17:44087739 A>G
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750416
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AAT to GAT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation was detected in a Dutch individual diagnosed with early onset frontotemporal dementia (Cohn-Hokke et al., 2014). Symptoms started at age 49, and included disinhibition, stereotyped and compulsive behavior, language impairment, and memory loss. Death occurred at age 62. Although segregation with disease could not be determined, this individual had a strong family history of dementia, consistent with autosomal-dominant transmission.

This variant was absent from the gnomAD public variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology

Neuropathological data are unavailable, but imaging of the proband showed temporal atrophy.

Biological Effect

In a cell-based minigene splicing assay, this variant increased exon 10 inclusion (Tubeuf et al., 2020). Its PHRED-scaled CADD score, which integrates diverse information in silico, was 28.6, above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Not Classified*

*This variant fulfilled several ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. N296D: Variant is in a mutational hot spot and within the microtubule assembly domain.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 19 Sep 2025

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References

Paper Citations

Cohn-Hokke PE, Wong TH, Rizzu P, Breedveld G, van der Flier WM, Scheltens P, Baas F, Heutink P, Meijers-Heijboer EJ, van Swieten JC, Pijnenburg YA. Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort. J Neurol. 2014 Nov;261(11):2085-92. Epub 2014 Aug 10 PubMed.
Tubeuf H, Charbonnier C, Soukarieh O, Blavier A, Lefebvre A, Dauchel H, Frebourg T, Gaildrat P, Martins A. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat. 2020 Oct;41(10):1811-1829. Epub 2020 Aug 16 PubMed.

Mutations

MAPT N296D

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