Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype Studied: Alzheimer's Disease
Position: (GRCh38/hg38):Chr17:46010346 G>A
Position: (GRCh37/hg19):Chr17:44087712 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs149280278
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: GTC to ATC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation was detected in a study of people of Spanish descent (Jin et al., 2012). It was detected in two of 176 people with Alzheimer's disease and absent in 534 controls. The two individuals with AD are described as having sporadic early onset AD (onset at 64.5 years) and familial late-onset AD (onset at 70.5 years). Further clinical information was not reported.

In the gnomAD variant database, this variant is reported at a global frequency of 0.00027, including 42 heterozygotes (v4.1.0, Apr 2024). Twenty heterozygotes were of admixed American ancestry reflecting a much higher frequency in this group (0.00036), and the rest were of non-Finnish European ancestry.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
The biological effects of this variant have been studied in several different experimental systems. In a cell-based, minigene splicing assay, it increased exon 10 skipping (Tubeuf et al., 2020). However, it does not appear to have an effect on microtubule dynamics, although its encoded amino acid resides in tau’s second microtubule-binding repeat. In human embryonic kidney (HEK293T) cells in the presence of the microtubule-stabilizing agent paclitaxel, binding of mutant tau with four microtubule-binding repeats (0N4R) to microtubules was similar to that of wildtype 0N4R tau (Xia et al., 2019). Moreover, in these cells, mutant tau did not fuel aggregation, either in the presence or absence of K18 tau fragments that seed aggregation (Xia et al., 2019). However, in a study using peptides containing tau repeats 2 and 3 (R2R3) in a thioflavin T‐based aggregation assay, the V287I peptide aggregated faster compared to the wildtype peptide (Goud et al., 2025). As assessed by atomic force microscopy, the mutant fibrils were shorter and fragmented compared to wildtype peptides.

This variant's PHRED-scaled CADD score (26.1), which integrates diverse information in silico, was above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

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References

Paper Citations

1. Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, Ibero-American Alzheimer Disease Genetics Group Researchers, Cruchaga C. Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
2. 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.
3. Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019 Nov 29;294(48):18488-18503. Epub 2019 Oct 24 PubMed.
4. Goud AC, Kozlov I, Skoupilová P, Malina L, Roy S, Das V. Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia. Protein Sci. 2025 Sep;34(9):e70240. PubMed.

Further Reading

No Available Further Reading