Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44051754 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to GCG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 3

Findings

This mutation was reported in a 41-year-old man who developed memory impairment and disturbed behavior at age 35 (Gallo et al., 2010). He was hospitalized at age 40, developed seizures, and became mute. A sister developed a similar dementia syndrome characterized by insidious onset, loss of social awareness, and absence of insight, starting around age 31 with personality changes and behavioral disturbances. However, she did not carry the V75A variant. Two other siblings, as well as the mother, were unaffected non-carriers. A paternal aunt and the paternal grandmother were affected by Alzheimer’s disease and Parkinson’s disease, respectively.

The variant was absent from 200 control samples (Gallo et al., 2010). It was reported at a frequency of 0.000016 in the gnomAD variant database, including a single heterozygote of European (non-Finnish) ancestry (gnomAD v4.0.0, Apr 2024).

Neuropathology

Frontotemporal atrophy was seen as well as fronto-mesial and parietal left hypoperfusion by CT, MRI and SPECT (Gallo et al., 2010).

Biological Effect

The biological effect of this variant is unknown. Its PHRED-scaled CADD score, which integrates diverse information in silico, was 13.34, below the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

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References

Paper Citations

1. Gallo M, Tomaino C, Puccio G, Frangipane F, Curcio SA, Bernardi L, Geracitano S, Anfossi M, Mirabelli M, Colao R, Vasso F, Smirne N, Maletta RG, Bruni AC. Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci. 2010 Feb;31(1):65-70. Epub 2009 Sep 19 PubMed.

Further Reading

No Available Further Reading