Overview

Pathogenicity: Frontotemporal Dementia : Benign, Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr17:45983475 T>G
Position: (GRCh37/hg19):Chr17:44060841 T>G
dbSNP ID: rs141120474
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to GGC
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant has been detected in individuals with Alzheimer's disease as well as in healthy controls. It is most likely a rare, non-pathogenic polymorphism.

The V224G variant was first reported in people of Spanish descent (Jin et al., 2012). It was found in three out of 176 AD cases and in one out of 139 controls. Of the three AD cases, one was described as having familial early onset AD and two had familial late-onset AD. In affected individuals, onset age ranged from 58.5 to 72.5 years. Further clinical details were not reported.

This variant was also found in an exome-sequencing study of Caucasian individuals. It was detected in two out of 141 people with late-onset AD and in one out of 179 controls without neuropathology. For the two people with AD, symptom onset occurred at age 74 and 88, respectively. APOE genotype was ε2/ε3 for both affected mutation carriers. Further clinical details were not reported (Sassi et al., 2014).

Most recently, this variant was detected in one out of 72 AD cases and in one out of 58 controls, the latter lacking in AD neuropathology postmortem. The ages of the mutation carriers were not reported, nor were details regarding their cognitive health (Frigerio et al., 2015).

This variant occurs in an exon that is excluded from most tau transcripts and 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 (224) is in reference to these isoforms, rather than to isoform Tau-F (P10636-8), which is conventionally used for naming mutations in tau.

Neuropathology

Unknown. At least three V224G variant carriers lacked AD neuropathology postmortem (Sassi et al., 2014; Frigerio et al., 2015).

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.

Other Citations

1. Frigerio et al., 2015

External Citations

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

Further Reading

No Available Further Reading