Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121577395 G>A
Position: (GRCh37/hg19):Chr11:121448104 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to TAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 25

Findings

The C1192Y variant was identified in a man diagnosed with early onset Alzheimer’s disease at age 59, three years after the onset of noticeable decline in memory function (Cao et al., 2021). At the time of diagnosis, his memory impairment was so severe that it led to loss of employment. MRI showed whole-brain atrophy that was particularly prominent in the medial temporal lobes and hippocampi. His APOE genotype is E3/E3.

The proband does not have a family history of dementia. His son and daughter are also heterozygous carriers of the SORL1 C1192Y variant, but their ages and cognitive status were not reported.

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Each CR contains six conserved cysteines. Variants resulting in an odd number of cysteines—either through substitution of one of these six cysteines or mutation of another residue to cysteine—may disrupt disulfide bridging. Based on domain mapping of disease mutations, Andersen and colleagues predicted that variants containing an odd number of cysteines in a CR domain (ONC variants) are highly likely to increase AD risk (Andersen et al., 2023): Approximately 40 percent of variants in LDLR linked to familial hypercholesterolemia are ONC variants, and ONC variants in LRP4 and LRP5 have been linked to Cenani–Lenz syndactyly syndrome and exudative vitreoretinopathy 4, respectively. Indeed, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 ONC variants significantly increased the risk of AD (OR = 6.31 95% CI: 2.45-16.24, p=5.1x10^-6; Fisher Exact test) (Andersen et al., 2023). C1192Y is an ONC variant.

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References

Paper Citations

1. Cao L, Zhu F, Qiu G. Early-onset Alzheimer's disease may be associated with sortilin-related receptor 1 gene mutation: A family report and review. Radiol Case Rep. 2021 Jan;16(1):30-34. Epub 2020 Oct 29 PubMed.
2. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. 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