Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121520783 A>AA
Position: (GRCh37/hg19):Chr11:121391492 A>AA
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Duplication
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 9

Findings

This single-nucleotide insertion causes a frameshift, leading to the introduction of a premature stop codon. The variant is classified as pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

In a group of 1255 cases and 1938 controls from the European Early Onset Dementia Consortium, a Belgian subject with early onset Alzheimer’s disease (age of onset 64 years) and a family history of AD was found to be a heterozygous carrier of this variant (Verheijen et al., 2016).

The variant was not seen in Dutch cohort of 640 cases and 1268 controls (Holstege et al., 2017), nor was it found in datasets from the Alzheimer’s Disease Sequencing Project, the Alzheimer Disease Exome Sequencing France project, or a cohort from the United Kingdom and North America (Campion et al., 2019 reporting on cohorts described by Campion et al., 2019; Bellenguez et al., 2017; and Sassi et al., 2016, respectively).

Functional Consequences

The truncated transcript resulting from the premature stop codon is expected to undergo nonsense-mediated mRNA decay. Indeed, reduced levels of SORL1 mRNA were found in lymphoblast cells from the G447Rfs carrier, compared with cells from a non-carrier (Verheijen et al., 2016).

SIFT predicted the mutation to be damaging (Verheijen et al., 2016).

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References

Paper Citations

1. 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.
2. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
3. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
4. Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.
5. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.

Further Reading

No Available Further Reading