Mutations

APP A713T

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PP2, PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, None
Reference Assembly: GRCh37/hg19
Position: Chr21:27264108 G>A
dbSNP ID: rs63750066
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCG to ACG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This variant is associated with a variable phenotype. Some mutation carriers exhibit clinical and neuropathological features typical of Alzheimer's disease, while others have a more complex presentation, with prominent cerebrovascular disease and cerebral amyloid angiopathy (CAA). Unaffected mutation carriers also have been documented, including a carrier who, at age 88 (Carter et al., 1992), was past the broad range of reported ages at onset (52-82 years, Rossi et al., 2004; Bernardi et al., 2009). Moreover, the allele count and frequency of this variant in the gnomAD database were relatively high. It has been classified by some researchers as a risk factor.  

A French study first reported this mutation in one of 130 people with probable AD, according to NINCDS-ADRDA criteria. The mutation carrier was a 64-year-old woman who experienced memory loss at age 59. She did not have a family history of dementia. The mutation was also detected in five unaffected relatives, including three over the age of 62, arguing against segregation with disease, although incomplete penetrance was offered as another potential explanation. In this family, the A713T G>A mutation was accompanied by a second G>A transition at codon 715, predicted to be silent. Because of the proximity of the two point mutations, the authors described their finding as a double point mutation (GCG.ACA.GTG to ACG.ACA.GTA) (Carter et al., 1992).

The A713T mutation was later reported in an Italian family affected by autosomal dominant AD and strokes (Rossi et al., 2004). The reported pedigree shows six individuals over three generations. DNA was available from three affected family members, and all were heterozygous carriers, suggesting segregation with disease. However, the ages of two unaffected non-carriers were not reported. For the three affected family members for whom details were known, onset ranged from 52 to 68 years of age, with death at 57 to 73 years. The proband developed cognitive decline at age 52 and also experienced stroke-like symptoms, such as temporary language disturbances and monoparesis, the partial loss of voluntary movement in a single limb. Autopsy showed features consistent with a diagnosis of AD, including widespread amyloid plaques and neurofibrillary tangles (Braak stage VI). CAA was also prominent.

Also in 2004, a Spanish group reported the A713T mutation in a 56-year-old-man with a seven-year history of progressive cognitive decline consistent with AD. His first symptoms were memory impairment and depression. His older brother was also affected by dementia, but a detailed family history was not reported, and segregation with disease could not be established (Armstrong et al., 2004).

More recently the A713T mutation was discovered in a large Italian family with both heterozygous and homozygous mutation carriers (Conidi et al., 2015). The pedigree of the “PEC family” shows eight affected individuals over six generations. This family is not known to be genealogically connected to other A713T pedigrees, but the authors speculate that the Italian families are most likely related based on haplotype analysis. Disease in this family was described as AD with cerebrovascular lesions. Three affected family members were shown to be homozygous for the mutation and two were heterozygous. Genotype did not affect onset age, which was comparable between heterozygotes (e.g., 62, 73) and homozygotes (e.g. 76, 70, 70). The mutation was absent in 400 control individuals from the same region of Italy.

This mutation was also identified in two unrelated women from the United Kingdom. Both were considered to be affected by sporadic early onset AD. One woman had neuropathologically confirmed AD, with onset at age 62. The other woman met clinical criteria for probable AD, with onset at age 61. Additional clinical details were not reported (Barber et al., 2015).

Importantly, this variant was found in 11 unrelated families of European descent based on prospective screening of unrelated patients in the French national reference center for young AD patients (CNRMAJ, Rouen) across 25 years (personal communication, Gaël Nicolas 2022). Analyses using different datasets as controls, revealed an increased prevalence of the variant in affected individuals compared with controls (odds ratio > 5 in all cases).

The allele count and frequency of this variant in the gnomAD database were 26 and 0.0092 percent, respectively (Koriath et al., 2018). Of note, 21 of 25 carriers in this database were of Latino/Admixed American ancestry (gnomAD v2.1.1, Oct 2021).

Neuropathology

The neuropathology associated with the A713T mutation is variable. Some cases accumulate pathology fairly typical of AD, notably atrophy of the cerebral cortex, and especially the temporal lobes, with widespread neurofibrillary tangles and amyloid plaques and minimal amyloid angiopathy (e.g., Armstrong et al., 2004). However, other cases exhibit prominent vascular involvement with prominent CAA and other vascular lesions (e.g., Rossi et al., 2004Bernardi et al., 2009Conidi et al., 2015).

In postmortem brain there was no change in the Aβ42/Aβ40 ratio (Armstrong et al., 2004). However, the plasma Aβ42/Aβ40 ratio was higher in asymptomatic mutation carriers than in non-mutation carrying relatives, due to a decrease in Aβ40 and an increase in Aβ42.

Biological Effect

Mouse neuroblastoma cells expressing this variant secreted about half the amount of Aβ40 compared with cells expressing wild-type APP, resulting in an elevated Aβ42/Aβ40 ratio (Hsu et al., 2020). In silico, the A713T mutation is predicted to be damaging (Conidi et al., 2015; CADD v1.6, Jan 2022).

This variant may be a risk factor. Koriath and co-workers predicted it had less than 10 percent penetrance due to its relatively high incidence in the gnomAD, and described it as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018). However, taking into account their functional results, Hsu and colleagues classified it as a risk factor (Hsu et al., 2020). The prevalence analyses in the French cohort described above (Nicolas 2022) are consistent with the latter.

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*This variant, found in multiple affected individuals and families, may be a risk factor, a condition outside the scope of the ACMG-AMP guidelines.

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. A713T: In cells, increased Aβ42/Aβ40, decreased Aβ40.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. A713T: Analyses of 11 unrelated families indicated increased prevalence of this variant in affected individuals (OR > 5).

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS1-P

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  A713T: Although the frequency of this variant is greater than expected for autosomal dominant disease, statistical analyses indicated increased prevalence in affected versus non-affected individuals (OR > 5). 

BS2-P

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. A713T: Although the variant has been observed in healthy individuals older than the expected age of onset, statistical analyses indicated increased prevalence in affected versus non-affected individuals (OR > 5).

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 09 May 2022

Comments

  1. We found that the A713T mutation segregated with disease in a large Italian family, strongly supporting the pathogenicity of this rare variant (Conidi et al., 2015). However, this mutation did not segregate with disease in a previously described family (Carter et al., 1992). Although we can only speculate, it may be that the four “healthy” A713T carriers in that family were, in fact, presymptomatic at age 62 and older (and in one case at age 88). Other studies have shown that carriers of this mutation exhibit a particularly variable age of symptom onset , ranging from 52 to 82 years (Rossi et al., 2004; Bernardi et al., 2009). It is also possible, as Carter and colleagues suggested, that genetic, epigenetic or environmental modifiers influence the penetrance of the A713T mutation.

    Of particular note, in the A713T family they studied, Carter and colleagues also detected a G>A transition in the codon for the nearby amino acid 715. This is a synonymous change and may simply be a rare polymorphism. It was not present in the Italian family we studied, nor reported in any of the other known A713T carriers. Given the apparent lack of segregation of A713T in the family studied by Carter, it is possible that the accompanying G>A transition at codon 715 may reduce the penetrance of the A713T mutation. It is increasingly recognized that “silent” mutations can have significant biological effects, and that synonymous codons are not necessarily equivalent (Berleant et al., 2009). 

    We observed that APP A713T increases the Aβ42/Aβ40 ratio in plasma (Conidi et al., 2015). Studies in cell culture may elucidate the effects of the mutation on APP processing, and whether the presence of the nearby silent mutation affects this.

    For reasons that are currently unclear, human carriers of A713T present with either classic Alzheimer’s pathology or prominent CAA with significant vascular lesions. It would be interesting to determine the pattern of amyloid pathology in a mouse model and to explore potential modifiers of that pathology.

    References:

    . Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.

    . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.

    . A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.

    . AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.

    . The genetic code--more than just a table. Cell Biochem Biophys. 2009;55(2):107-16. Epub 2009 Jul 29 PubMed.

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
  2. . A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.
  3. . AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.
  4. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.
  5. . Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.
  6. . Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease. Neurobiol Aging. 2016 Mar;39:220.e1-7. Epub 2015 Dec 29 PubMed.
  7. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  8. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
  2. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.