Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121607229 G>T
Position: (GRCh37/hg19):Chr11:121477938 G>T
dbSNP ID: rs774446927
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AGG to ATG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 37

Findings

The R1702M variant was identified in an Alzheimer’s patient from a Spanish family with several members afflicted with AD (Gómez-Tortosa et al., 2018). The proband, her sister, maternal aunt, and a maternal cousin were affected, with ages of symptom onset ranging from 70 to 82 years. (The proband’s mother died before age 50, at which time she was unaffected.) In addition to dementia of the Alzheimer’s type, the proband also developed mild parkinsonism late in her disease course.

Thus far, the mutation segregates with disease within the family, although data are limited: In addition to the proband, genotype data were available from two unaffected maternal cousins, ages 84 and 79, neither of whom carried the mutation. The proband was homozygous for the E3 allele of APOE.

This variant was found in one of 200 elderly Spanish control subjects, a 75-year-old man.

The R1702M variant is classified as likely benign by the criteria of Holstege and colleagues (Holstege et al., 2017) and by the American College of Medical Genetics and Genomics guidelines (Gómez-Tortosa et al., 2018).

Functional Consequences

The variant is predicted to be damaging by PolyPhen-2.

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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