Mutations

SORL1 R416Q

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121520692 G>A
Position: (GRCh37/hg19):Chr11:121391401 G>A
dbSNP ID: rs377550239
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGA to CAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 9

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 three times—twice among the AD cases and once among the controls (Holstege et al., 2022).

The R416Q variant was reported previously in a cohort of North American and British Caucasians, where it was found in one of 332 AD cases and one of 676 controls (Sassi et al., 2016). In a group of European-Americans with a family history of late-onset AD, the variant was found in two of 875 cases and one of 328 controls (Fernández et al., 2016). The variant did not associate with risk of AD in either of these studies.

This variant was among 54 selected for genotyping in a North American cohort of 217 sporadic early onset AD cases and 169 controls. It was not found in these subjects (Fernández et al., 2016).

A carrier of the R416Q variant was identified among a group of patients with clinician-diagnosed early onset dementia seen at the Memory Disorders Clinic at the University of Alabama at Birmingham (Cochran et al., 2019). The carrier, diagnosed with mild dementia of unclear etiology, began experiencing symptoms in his or her mid-50s and has a “strong” family history of dementia—defined in this study as at least three people in two generations affected with early onset AD, FTLD, ALS, CBD, or PSP, and with one person being a first-degree relative of the other two. This individual is APOE E3/E4 and also carries a coding variant in the membrane metalloendopeptidase (MME) gene.

Functional Consequences

The arginine-to-glutamine substitution at amino acid 416 was predicted to be damaging by SIFT, PolyPhen-2, and Mutation Taster (Campion et al., 2019; Cochran et al., 2019; Fernández et al., 2016; Sassi et al., 2016).

Table

Risk Allele(s) N
Cases | Controls
aAllele frequency
Cases | Controls
Reported association measurements Ancestry
(Cohort)
Reference
Mega-analysis
A 15,808 | 16,097 3.16×10-5 | 6.21×10-5   Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
A 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 0 | 0 | 0   French
(Alzheimer Disease Exome Sequencing France (ADESFR))
Bellenguez et al., 2017, Campion et al., 2019
A 5198 | 4491 0 | 0   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))
Campion et al., 2019
A sporadic EOAD
217 | 169
0 | 0   European American
(Knight ADRC)
Fernández et al., 2016
familial LOAD
875 | 328
1.16×10-3 | 1.54×10-3 OR = 0.748
[CI: N.A.]
p = 0.1573
European American
(Knight ADRC, NIA-LOAD)
A 640 | 1268 0 | 0   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)
Holstege et al., 2017,
Campion et al., 2019
A 332 | 676 1.51 ×10-3 | 7.34 ×10-4 OR = 2.037
[0.0259-160.108]
p = 0.55
UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)
Sassi et al., 2016
A 1255 | 1938 0 | 0   European
(European Early-Onset Dementia Consortium)
Verheijen et al., 2016,
Campion et al,. 2019

aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

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. . 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. . SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
  4. . Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles. Cold Spring Harb Mol Case Stud. 2019 Dec;5(6) Print 2019 Dec PubMed.
  5. . 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.
  6. . 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.
  7. . 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.
  8. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.

Other mutations at this position

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