Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype Studied: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr17:45983475 T>G
Position: (GRCh37/hg19):Chr17:44060841 T>G
Transcript: NM_016835; ENST00000571987
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. In the gnomAD public variant database, it was reported at a global frequency of 0.0032, and was most frequent in individuals of non-Finnish European ancestry, rare in South Asian individuals, and absent in East Asians (gnomAD v4.1.0, Apr 2024).

The V224G variant was first reported in people of Spanish descent (Jin et al., 2012). It was found in three of 176 AD cases and in one 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 of 141 people with late-onset AD and in one of 179 controls without neuropathology. For the two people with AD, symptom onset occurred at age 74 and 88, respectively. APOE genotype was E2/E3 for both affected mutation carriers. Further clinical details were not reported (Sassi et al., 2014).

In addition, this variant was detected in one of 72 AD cases and in one 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 (Sala Frigerio et al., 2015).

V224G is located in exon 4a, which is excluded from the six major tau isoforms expressed in the human brain. Exon 4a is included in PNS-tau, a tau isoform expressed in the peripheral nervous system which is used here as the reference isoform for naming the variant.

The biological effect of this variant is unknown. Although it was predicted to be “possibly damaging” by the SIFT/Polyphen algorithms (Sassi et al., 2014), its PHRED-scaled CADD score, which integrates diverse information in silico, was 18.29, below the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, April 2024). Sassi and colleagues classified this variant as benign and Sala Frigerio and co-workers described it as a possible risk factor.

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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. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Nov;11(11):1265-76. Epub 2015 Apr 29 PubMed.

Further Reading

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