Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27269944 G>C
dbSNP ID: rs1259157720
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to CTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

This mutation was found in a Korean woman diagnosed with early onset Alzheimer’s disease. During her initial visit to the hospital for a memory complaint at age 56, she reported experiencing symptoms for about two years, beginning with disorganization, problems with decision-making, and declining performance at work. Neuropsychological testing revealed deficits in memory and executive function, and an MRI showed mild brain atrophy, most pronounced in the temporal lobe and including the hippocampus. A year after her first clinic visit, her husband reported that she was no longer able to perform activities of daily living; at this time, MRI showed severe atrophy of the cortex and hippocampus and FDG-PET showed hypometabolism in temporoparietal regions. Her condition continued to worsen: She developed generalized seizures, and was mute and bedridden within four years.

Cerebrospinal fluid biomarkers were not measured in this patient, although levels of Aβ oligomers in her blood were approximately 50 percent higher than those seen in a control population.

There may be a family history of dementia. The proband’s mother reportedly experienced similar cognitive decline, with symptom onset in her 50s, and one of the mother’s three siblings may have been affected also.

The proband’s two half-sisters, unaffected at ages 48 and 59 years, did not carry the mutation.

The V669L mutation was not found in the 1000 Genomes, ExAC, gnomAD, or KRGDB (Korean Reference Genome Database) databases.

This mutation is classified as possibly pathogenic according to the algorithm of Guerreiro et al. (Guerreiro et al., 2010).

Biological Effect

Amino acid 669 in APP is three amino acids N-terminal to the BACE cleavage site (the “P3” position), and immediately adjacent to the site of the Swedish mutation (KM670/671NL). The effect of the valine-to-leucine substitution on BACE cleavage has yet to be tested experimentally, but it should be noted that this mutation does not result in major changes in hydrophobicity or bulkiness at this residue (Bagyinszky et al., 2019), two features at the P3 position that are reportedly key for BACE substrates  (Grüninger-Leitch et al., 2002).  However, three-dimensional modeling showed that amino acid 669 is located in the random-coil region of APP and that the V669L mutation may result in changes in intramolecular interactions within this region (Bagyinszky et al., 2019).

Although PolyPhen2 and SIFT predicted that the mutation would be benign, and PROVEAN classified this as a neutral variant (Bagyinszky et al., 2019), the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
2. Bagyinszky E, Kang MJ, Van Giau V, Shim K, Pyun JM, Suh J, An SS, Kim S. Novel amyloid precursor protein mutation, Val669Leu ("Seoul APP"), in a Korean patient with early-onset Alzheimer's disease. Neurobiol Aging. 2019 Dec;84:236.e1-236.e7. Epub 2019 Aug 31 PubMed.
3. Grüninger-Leitch F, Schlatter D, Küng E, Nelböck P, Döbeli H. Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J Biol Chem. 2002 Feb 15;277(7):4687-93. PubMed.

Other Citations

1. Swedish mutation

Further Reading

No Available Further Reading