Mutations

SORL1 T1002M

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121559613 C>T
Position: (GRCh37/hg19):Chr11:121430322 C>T
dbSNP ID: rs368806137
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 21

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 five times—twice among the AD cases and three times among the controls (Holstege et al., 2022). A mega-analysis of these data did not find an association between the variant and AD risk.

Previously, two Belgian control subjects (ages 65 and 81 years) were found to be heterozygous carriers of this variant, in a cohort of 1255 Alzheimer’s cases and 1938 controls from the European Early-Onset Dementia Consortium (Verheijen et al., 2016).

Subsequently, this variant was reported in one of 4491 controls but none of 5198 AD cases 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). The ADSP contributed to the 2022 study cited above.

The T1002M variant was selected for genotyping in a North American sample of 217 sporadic early onset AD cases and 169 controls, based on its occurrence in the Exome Variant Server database as a nonsynonymous variant with a minor allele frequency of less than 5 percent. The variant was not found in this cohort (Fernández et al., 2016).

(See table for other datasets in which the absence of this variant was documented.)

This variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

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

Table

Risk Allele(s) N
Cases | Controls
aAllele frequency
Cases | Controls
Reported association measurements Ancestry
(Cohort)
Reference(s)
Large-scale studies, meta- and mega-analyses
T 15,808 | 16,097 6.32×10-5 | 9.32×10-5 OR = 0.63
[CI: 0.10-4.04]
p = 0.63
Multiple European and American cohorts Holstege et. al., 2022
(mega-analysis)
Other studies
T 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 0 | 0 | 0   French
(Alzheimer Disease Exome Sequencing France (ADESFR))
Bellenguez et al., 2017; Campion et al., 2019
T 5198 | 4491 0 | 1.11×10-4   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))
Campion et al., 2019
T sporadic EOAD
217 | 169
0 | 0   European American
(Washington University Knight ADRC)
Fernández et al., 2016
T 640 | 1268 0 | 0  

Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)

Holstege et al., 2017
T 332 | 676 0 | 0   UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)

Sassi et al., 2016;
Campion et al., 2019

T 1255 | 1938 0 | 5.16×10-4   European
(European Early-Onset Dementia Consortium)
Verheijen et al., 2016

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. . 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. . 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. . SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
  5. . 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.
  6. . 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.
  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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.

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