Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121496917 T>C
Position: (GRCh37/hg19):Chr11:121367626 T>C
dbSNP ID: rs12364988
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: CAT to CAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 6

Findings

This synonymous variant has been found in both heterozygous and homozygous states in multiple ancestries, with the C and T alleles occurring with nearly equal frequencies in several studies. A large meta-analysis of data sets from the International Genomics of Alzheimer’s Project did not find an association between the H269H variant and risk for AD (Liu et al., 2017). A few smaller studies did report an association between this variant and AD, although the findings were not consistent: The T allele was associated with an increased risk of AD in a group of individuals of North European descent and in an Israeli-Arab cohort (Rogaeva et al., 2007), while the C allele was associated with increased risk of AD in an Italian study (Cellini et al., 2009) and decreased risk in a neuropathologically-confirmed sample in Japanese ADNI (Wen et al., 2013).

The possible association of the H269H variant with Alzheimer’s-related endophenotypes was examined in several studies. The variant was not found to be associated with brain atrophy (Cuenco et al., 2008; Louwersheimer et al., 2015; Yin et al., 2016), cognitive assessments (Louwersheimer et al., 2015; Reynolds et al., 2013), cerebrospinal fluid biomarkers (Louwersheimer et al., 2015), or MRI markers of cerebrovascular disease (Cuenco et al., 2008) in older adults (> 60 years of age).

The variant did not associate with hippocampal volume in healthy young adults (ranging from 18 to 36 years of age) (Bralten et al., 2011).

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

Linkage Disequilibrium

SNP 7 was found to be in linkage disequilibrium with several other variants, including rs560573 (SNP 6), rs668387 (SNP 8), rs689021 (SNP 9), and rs641120 (SNP 10) in cohorts of European ancestry (Rogaeva et al., 2007; Young et al., 2015); rs560573 (SNP 6) and rs668387 (SNP 8) in an African American family dataset (Rogaeva et al., 2007); and rs560573 (SNP 6), rs668387 (SNP 8), rs689021 (SNP 9), rs641120 (SNP 10), and rs4935775 (SNP 11) in a Hispanic family dataset (Rogaeva et al., 2007).

Functional Consequences

The variant was predicted to be tolerated by SIFT and neutral by PROVEAN, and was classified as a polymorphism by Mutation Taster (El Bitar et al., 2019).

Levels of wild-type and H269H SORL1 transcripts were similar in the prefrontal cortices in autopsy specimens from AD donors, suggesting that this variant is not linked to regulation of expression of SORL1 (Alachkar et al., 2008).

Table

^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.

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References

Paper Citations

1. Liu G, Sun JY, Xu M, Yang XY, Sun BL. SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. J Alzheimers Dis. 2017;58(4):1121-1128. PubMed.
2. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
3. Cellini E, Tedde A, Bagnoli S, Pradella S, Piacentini S, Sorbi S, Nacmias B. Implication of sex and SORL1 variants in italian patients with Alzheimer disease. Arch Neurol. 2009 Oct;66(10):1260-6. PubMed.
4. Wen Y, Miyashita A, Kitamura N, Tsukie T, Saito Y, Hatsuta H, Murayama S, Kakita A, Takahashi H, Akatsu H, Yamamoto T, Kosaka K, Yamaguchi H, Akazawa K, Ihara Y, Kuwano R. SORL1 is genetically associated with neuropathologically characterized late-onset Alzheimer's disease. J Alzheimers Dis. 2013;35(2):387-94. PubMed.
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11. Young JE, Boulanger-Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, Herrera C, Israel MA, Yuan SH, Edland SD, Goldstein LS. Elucidating molecular phenotypes caused by the SORL1 Alzheimer's disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell. 2015 Apr 2;16(4):373-85. Epub 2015 Mar 12 PubMed.
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Further Reading

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