Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121583514 C>T
Position: (GRCh37/hg19):Chr11:121454223 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CCC to TCC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 26

Findings

The P1213S variant was identified in a Saudi Arabian Alzheimer’s patient who began exhibiting symptoms at age 64 (El Bitar et al., 2019). This patient displayed disorientation, impaired learning and recall of recent information, worsening cognition, and mild brain atrophy. His mother and three of his siblings were also affected, with ages of symptom onset ranging from 54 to 60 years.

The proband and one sister, unaffected at 53 years of age, are heterozygous carriers of this variant. The proband is homozygous for the E4 allele of APOE. Genotype data from other family members were unavailable.

The variant was not found in the ExAC or 1000 Genomes databases at the time of its publication, but it occurred with a minor allele frequency of 0.00158 in the Saudi Human Genome Program Local Control database (El Bitar et al., 2019).

Functional Consequences

Proline-1213 is located in the fourth of SORL1’s 11 complement-type repeat (CR)-domains (also called “LDLR-type A repeats”) and is conserved among vertebrate species. In silico modeling demonstrated that the proline-to-serine substitution caused a change in protein folding and secondary structure. The mutation was predicted to be disease-causing by Mutation Taster, probably damaging by Polyphen-2, tolerated by SIFT, and deleterious by PROVEAN (El Bitar et al., 2019).

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References

Paper Citations

1. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.

Further Reading

No Available Further Reading