Mutations

SORL1 R814H

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121555188 G>A
Position: (GRCh37/hg19):Chr11:121425897 G>A
dbSNP ID: rs372764840
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 18

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed four times—three times among the AD cases and once among the controls (Holstege et al., 2022).

The R814H variant previously was reported in a European-American dataset composed of 875 cases with familial late-onset AD and 328 controls (Fernández et al., 2016). The minor allele frequencies in the cases and controls were 2.89×10-3 and 1.54×10-3, respectively, and the variant did not associate with AD risk in this sample.

This variant also was found in one of 5198 AD cases and none of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project (ADSP), consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019). ADSP contributed data to the 2022 study cited above.

Functional Consequences

Arginine-814 is found within the YWTD-repeated β-propeller domain (Andersen et al., 2023). Arginines are found at equivalent positions in five of the six blades of the YWTD-repeated β-propeller, where they are thought to interact with the tyrosines of the YWTD motifs to stabilize the domain. Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of arginine-814 are highly likely to increase the risk of Alzheimer’s disease—variants in homologous positions in LRP5 are found in patients with osteoporosis-pseudoglioma syndrome and exudative vitreoretinopathy, in LRP4 in patients with congenital myasthenic syndrome, and a mutation in LRP6 segregated with disease in a family with metabolic syndrome.

This variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Campion et al., 2019).

Last Updated: 18 Jul 2024

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References

Paper Citations

  1. . Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
  2. . SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
  3. . 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. . 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

Protein Diagram

Primary Papers

  1. . 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. . 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.

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