Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, BS2, BS3, BP4
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46010295 T>C
Position: (GRCh37/hg19):Chr17:44087661 T>C
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Codon Change: T to C
Genomic Region: Intron 9

Findings

This intronic mutation was detected in an apparently sporadic case of frontotemporal dementia (FTD; Anfossi et al., 2011), later classified as the behavioral variant of FTD (Moore et al., 2020, suppl materials). The proband developed changes in personality and behavior at age 46, including apathy, disinhibition, depression, and aggressive behavior (Anfossi et al., 2011). Her spontaneous speech decreased, and she later became mute. She developed progressive cognitive decline, followed by extrapyramidal signs and myoclonus. She died at age 57. She did not have a family history of disease. In addition to this novel mutation in intron 9, the proband also carried a novel variant in intron 10 (IVS10+4 A>C). The extent to which these two MAPT variants contribute to disease is unknown. The proband's sister is the only other person known to carry both variants, and she was cognitively healthy at age 58 with only mild problems in attention and memory. Family members who carried only one of the two variants were cognitively healthy.

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

Neuropathology

Autopsy showed severe atrophy of the frontotemporal lobes with relative sparing of the motor and visual cortices. There was atrophy of the caudate nucleus and substantia nigra. The hippocampus was severely affected by neuronal loss, with a band of dense astrocytic gliosis where neurons should have been. Abundant tau pathology was observed throughout the brain, primarily comprised of three-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles were noted in the cortex.

Biological Effect

When co-transfected with wild-type tau, this mutation did not significantly affect exon 10 splicing. However, when co-transfected with the IVS10+4 A>C mutation, a significant reduction in transcripts containing exon 10 was observed. The increase in transcripts lacking exon 10 resulted in an overproduction of three-repeat (3R) tau isoforms relative to 4R isoforms.

This variant's PHRED-scaled CADD score (15.72), which integrates diverse information in silico, was below the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Not Classified*

*This variant may be pathogenic when co-inherited with another MAPT intronic variant (IVS10+4 A>C).

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

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-P

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. IVS9-15 T>C: This variant did not significantly affect exon 10 splicing on its own, but reduced exon 10 transcripts in the presence of IVS10+4 A>C.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 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: 27 Oct 2025

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References

Paper Citations

Anfossi M, Vuono R, Maletta R, Virdee K, Mirabelli M, Colao R, Puccio G, Bernardi L, Frangipane F, Gallo M, Geracitano S, Tomaino C, Curcio SA, Zannino G, Lamenza F, Duyckaerts C, Spillantini MG, Losso MA, Bruni AC. Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia. Neurobiol Aging. 2011 Apr;32(4):757.e1-757.e11. Epub 2011 Feb 3 PubMed.
Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.

Mutations

MAPT IVS9-15 T>C

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