Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121570204 A>G
Position: (GRCh37/hg19):Chr11:121440913 A>G
dbSNP ID: rs139794846
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to GTC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 23

Findings

In a European American cohort of 134 sporadic late-onset Alzheimer’s cases and 266 controls, one AD case and one control were heterozygous carriers of this variant (Fernández et al., 2016). In a second study of Caucasian subjects from Britain and North America, one of 676 controls and none of 332 AD cases carried the variant (Sassi et al., 2016). The variant did not associate with disease in either of these studies.

No additional carriers were found among 5198 AD cases and 4491 controls from the Alzheimer’s Disease Sequencing Project from whom whole-exome sequencing data were available, 1779 AD cases and 1273 controls from the Alzheimer Disease Exome Sequencing France project, 640 cases and 1268 controls from a multi-center Dutch sample, or 1256 cases and 1938 controls from the European Early Onset Dementia Consortium (Campion et al., 2019).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Isoleucine-1091 is one of a pair of conserved hydrophobic amino acids—usually isoleucine and phenylalanine—in the N-terminal part of each CR that help to stabilize this region. Andersen and colleagues predicted that substitutions of one of these hydrophobic amino acids are moderately likely to increase AD risk (Andersen et al., 2023). However, as the I1091V variant substitutes one hydrophobic amino acid for another, it may be tolerated.

The variant was predicted to be tolerated by SIFT, disease-causing by Mutation Taster, and benign by PolyPhen-2 (Sassi et al., 2016).

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References

Paper Citations

1. Fernández MV, Black K, Carrell D, Saef B, Budde J, Deming Y, Howells B, Del-Aguila JL, Ma S, Bi C, Norton J, Chasse R, Morris J, Goate A, Cruchaga C, NIA-LOAD family study group, NCRAD. SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
2. 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.
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. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

Further Reading

No Available Further Reading