Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121555270 G>A
Position: (GRCh37/hg19):Chr11:121425999 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TAG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 18

Findings

This protein-truncating variant was identified in a screen of 124 Alzheimer’s patients with a family history of AD (at least one affected first-degree relative) recruited from a memory clinic in Madrid (Gómez-Tortosa et al., 2018). The carrier began exhibiting symptoms at 58 years of age and was 72 years old at the time of publication of her mutation. She is homozygous for the E4 allele of APOE. DNA was available from one unaffected sibling of the proband, and this individual does not carry the variant.

The variant was absent from a control group of 200 Spanish individuals 69 to 95 years of age.

The W848Ter variant is classified as pathogenic by the criteria of Holstege et al. (Holstege et al., 2017) and as likely pathogenic by the guidelines of the American College of Genetics and Genomics.

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References

Paper Citations

1. Gómez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Pérez B, Ordás C, Agüero P, Guerrero-López R, Pérez-Pérez J. SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. PubMed.
2. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.

Further Reading

No Available Further Reading