Overview

Pathogenicity: : Not Classified
Clinical Phenotype Studied: None
Position: (GRCh38/hg38):Chr17:45983403 G>A
Position: (GRCh37/hg19):Chr17:44060769 G>A
Transcript: NM_016835; ENST00000571987
dbSNP ID: rs757159453
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to GAG
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant was detected in one control individual in an exome sequencing study of 141 Caucasian individuals with late-onset Alzheimer’s disease and 179 elderly Caucasian controls without neuropathology (Sassi et al., 2014). In the gnomAD public variant database, it was reported at a global frequency of 0.000033, including 48 heterozygotes, most of non-Finnish European ancestry (gnomAD v4.1.0, Apr 2024).

G200E 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.

Neuropathology

Not applicable.

Biological Effect

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 only 2.78, well below the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, April 2024). Sassi and colleagues classified this variant as benign.

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References

Paper Citations

1. 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.

Further Reading

No Available Further Reading