Mutations

SORL1 S2175R (C>G)

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121627715 C>G
Position: (GRCh37/hg19):Chr11:121498424 C>G
dbSNP ID: rs143536682
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to AGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 47

Findings

This rare variant has been found in both Alzheimer’s patients and non-affected individuals of European ancestry. 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 20 times—ten times among the AD cases and ten times among the controls (Holstege et al., 2022). Mega-analysis of these data did not find an association between the variant and AD risk. An additional control carrier was found when this dataset was expanded to 18,959 AD cases and 21,893 controls (Holstege et al., 2023).

Functional Consequences

Serine-2175 is located in SORL1’s cytoplasmic tail, within the 2172FANSHY2177 motif, a strictly conserved sequence necessary for binding the retromer complex (Fjorback et al., 2012). Andersen and colleagues have predicted that substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023).

Data on the functional consequences of substitutions at this specific residue are lacking. However, in vivo and in vitro studies showed that when the FANSHY domain was mutated to disrupt retromer binding, SORL1 accumulated in endosomes and was depleted from the Golgi/trans-Golgi network, while levels of APP cleavage products Aβ40, Aβ42, sAPPα, and sAPPβ increased (Fjorback et al., 2012; Dumanis et al., 2015). These findings can be explained if retromer-dependent sorting of SORL1 and its ligand APP from endosomes back to the Golgi/trans-Golgi network protects APP from processing in endosomal compartments.

The variant was predicted to be deleterious by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Bellenguez et al., 2017; Sassi et al., 2016).

Table

Risk Allele(s) N
Cases | Controls
aAllele frequency
Cases | Controls
Reported association measurements Ancestry
(Cohort)
Reference
Large-scale studies, meta- and mega-analyses
G 15,808 | 16,097 3.16×10-4 | 3.11×10-4 OR = 0.73
[CI: 0.29-1.85]
p = 0.49
Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
G 18,959 | 21,893 2.64×10-4 | 2.51×10-4   bMultiple European and American cohorts Holstege et al., 2023
Other studies
G 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 5.92×10-4 | 0 | 0   French
(Alzheimer Disease Exome Sequencing France (ADESFR))
Bellenguez et al., 2017
G 5198 | 4491 3.85×10-4 | 5.57×10-4   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))
Campion et al., 2019
G sporadic EOAD
217 | 169
0 | 0   European American
(Knight ADRC)
Fernández et al., 2016
familial LOAD
875 | 328
0 | 0   European American
(Knight ADRC, NIA-LOAD)
G 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
G 332 | 676 0 | 7.396×10-4 OR = 0
[CI: 0- 79.31]
p = 1
UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)
Sassi et al., 2016
G 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.
bAddtional subjects added to the dataset reported by Holstege et al., 2022.

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. . Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
  3. . 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.
  4. . 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.
  5. . SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
  6. . 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.
  7. . 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.
  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.
  9. . Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. PubMed.
  10. . 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.
  11. . Distinct Functions for Anterograde and Retrograde Sorting of SORLA in Amyloidogenic Processes in the Brain. J Neurosci. 2015 Sep 16;35(37):12703-13. 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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