Mutations

SORL1 M105T

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121470035 T>C
Position: (GRCh37/hg19):Chr11:121340744 T>C
dbSNP ID: rs982581946
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ACG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 2

Findings

Carriers of the M105T variant—all cognitively impaired—were reported in multiple studies, some of which have drawn from the same datasets. As mentioned below, there is an allusion to non-affected carriers in a study that examined segregation with disease in a single family, but no further details were provided.

This variant was first reported in a study of British and North American Caucasians, where it was found in one of 332 Alzheimer’s cases and none of 676 controls; its association with AD did not reach statistical significance in this study (Sassi et al., 2016).

Subsequently, this variant was found in a genome-sequencing study of patients with early onset dementia attending the Memory Disorders Clinic at the University of Alabama at Birmingham (Cochran et al., 2019). The carrier was diagnosed with Alzheimer’s disease with symptom onset in their mid-50s, and had an APOE genotype E3/E4 and a “strong” family history of AD—defined in this study as at least three people in two generations affected with early onset AD, with one person being a first-degree relative of the other two. The variant did not completely segregate with disease in four family members of the proband (further details about ages, clinical, and carrier status were not provided in this report).

Cochran and colleagues screened several other datasets for the M105T variant and calculated a replication-only odds ratio: In addition to the carrier identified by Sassi et al., they found five carriers in the Alzheimer’s Disease Sequencing Project (ADSP); four of these carriers were diagnosed with AD and the remaining carrier was classified as having mild cognitive impairment. No carriers were identified in four other studies: Vardarajan et al., 2015 (Caribbean Hispanics, Canadians of Northern European origin); Fernández et al., 2016 (Knight Alzheimer’s Disease Research Center at Washington University, St. Louis; and National Institute on Aging Genetics Initiative for Late-Onset Alzheimer’s Disease); Verheijen et al., 2016 (European Early Onset Dementia Consortium); Bellenguez et al., 2017 (Alzheimer Disease Exome Sequencing France (ADESFR) project). The six carriers were found among a total of 13,390 AD cases, compared with 11 carriers among 189,196 individuals in population-level genetic databases, for an odds ratio of 7.7 (p = 0.0005).

The M105T variant also was reported in two of 5198 AD cases and none of 4491 controls in a dataset from the ADSP restricted to subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including ADSP, ADESFR, and the Knight ADRC, this allele was observed eight times among the AD cases (Holstege et al., 2022).

Functional Consequences

Amino acid 105 is within the VPS10P domain of SORL1, the region of the protein shown to bind Aβ (Caglayan et al., 2014). Computational modeling conducted by Cochran et al. showed that methionine-105 is highly conserved and that the methionine-to-threonine substitution may introduce a phosphorylation site for the serine/threonine kinase PLK1 (Cochran et al., 2019).

The methionine-to-threonine substitution at amino acid 105 was predicted to be possibly damaging by PolyPhen-2, deleterious by SIFT, and disease-causing by Mutation Taster (Sassi et al., 2016).

Last Updated: 18 Jul 2024

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References

Paper Citations

  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.
  2. . 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.
  3. . Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. 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. . 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.
  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. . 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.
  8. . 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.
  9. . Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation. Sci Transl Med. 2014 Feb 12;6(223):223ra20. 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.

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