Overview

Pathogenicity: Frontotemporal Dementia : Benign, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr17:45983441 G>A
Position: (GRCh37/hg19):Chr17:44060807 G>A
dbSNP ID: rs76375268
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to AGG
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant was reported in a study of individuals of Spanish descent (Jin et al., 2012). It was detected in one out of 176 cases with Alzheimer's disease and absent in 139 controls. The mutation carrier was described as having sporadic early onset AD, with onset at age 64.5. Further clinical details were not reported.

This variant was also detected in an exome-sequencing study of Caucasian individuals. It was found in two of 141 cases with late-onset AD and in one out of 179 controls without neuropathology. In the two individuals with AD, symptom onset occurred at 74 and 75 years of age. Further clinical details were not available. APOE genotypes were ε3/ε4 and ε3/ε3 (Sassi et al., 2014).

Note that this variant occurs in an exon excluded from most tau transcripts and it is therefore not represented in most isoforms. However, it is present in longer isoforms such as PNS-tau (P10636-1) and Tau-G (P10636-9), which are 758 and 776 amino acids long, respectively. Therefore, the position of this variant is in reference to these isoforms, rather than to isoform Tau-F (P10636-8), which is conventionally used for naming mutations in tau.

Neuropathology

Not applicable.

Biological Effect

Unknown. In silico, this variant is predicted to be “possibly damaging.” It is classified as a benign polymorphism according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014).

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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. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Al-Sarraj S, Niblock M, Gallo JM, Adnan J, Killick R, Brown KS, Medway C, Lord J, Turton J, Bras J, Alzheimer's Research UK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.
3. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

External Citations

1. P10636-1
2. P10636-9
3. P10636-8

Further Reading

No Available Further Reading