ClinVar Genomic variation as it relates to human health

The p.Ala713Thr variant in APP has been reported in 16 probands with Alzheimer disease and segregated in 8 affected family members (Carter 1992, Rossi 2004, Amstrong 2004, Bernandi 2009, Pera 2013, Conidi 2015, Barber 2016, Lanoiselee 2017, Koriath 2018). In one family with 6 affected individuals, all 3 living affected harbored the variant and 6 of 24 unaffected members (1 over the age of 65) carried the variant (Rossi 2004). In another family the variant was also present in 5 unaffected members (3 over the age of 62) (Carter 1992). In a third family there was one additional affected family member, however, the carrier status was not determined (Amstrong 2004). In 3 additional families the probands presented with late onset Alzheimer disease associated with cerebrovascular lesions. Other family members were reportedly affected with dementia; however their carrier status for the p.Ala713Thr variant was not documented (Bernandi 2009). In another multigenerational family, the variant was found in 5 patients (2 heterozygous and 3 homozygous) and in 6 asymptomatic at risk individuals (Conidi 2015). This variant has also been identified in 21/34414 (0.061%) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 18094). Computational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant exists in a region of the protein where other pathogenic variants cluster and is a known site for protein cleavage. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala713Thr variant is likely pathogenic albeit with reduced and age-related penetrance. ACMG/AMP Criteria applied:PP1_Strong, PM1, PP3.

Variant summary: APP c.2137G>A (p.Ala713Thr) results in a non-conservative amino acid change located in the Amyloidogenic glycoprotein, amyloid-beta peptide (IPR013803) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251384 control chromosomes with 24 heterozygotes in GnomAD. c.2137G>A has been reported in the literature in multiple individuals affected with Autosomal dominant Alzheimer Disease and/or cerebrovascular lesion (examples, Carter_1992, Rossi_2004, Armstrong_2004, Bernardi_2009, Moro_2012, Pera_2013, Conidi_2014, Barber_2016, Lanoiselee_2017). Most of patients had a family history of Alzheimer Disease, and the clinical presentation featured with a progressive cognitive decline with a wide range of onset ages (49 to 85 years-old). Particularly, the variant was reported at a homozygous state in 3 patients from a consanguineous family with Alzheimer Disease and cerebrovascular lesion, and the clinical outcome and disease onset were not different from the heterozygous carriers from the same family (Conidi_2014). Meanwhile, multiple asymptomatic carriers were reported, including one 88-years-old woman (example, Carter_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which suggest this variant resulted in a significant increase in the Beta amyloid 42/40 ratio compared with WT in N2A cells via ELISA, the total amount of Beta amyloid was however reduced (Hsu_2020). Such results does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 15488330, 24278680, 19363265, 1303275, 25948718, 32087291, 28350801, 23143229, 23224319, 15365148). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=3, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APP function (PMID: 29459625). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APP protein function. ClinVar contains an entry for this variant (Variation ID: 18094). This missense change has been observed in individual(s) with Alzheimer's disease and a positive family history of the disorder, although many of these individuals did not have early onset of disease. In addition, it has been reported in the heterozygous state in 2 affected individuals and the homozygous state in 3 affected individuals from a single consanguineous family (PMID: 15365148, 15488330, 19363265, 23224319, 25948718, 26803359, 28350801). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750066, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the APP protein (p.Ala713Thr).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0101 – Toxic gain of function is a known mechanism of disease in this gene and is associated with cerebral amyloid angiopathy (MIM#605714) and familial Alzheimer disease 1 (MIM#104300) (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Specifically, the p.(Ala713Thr) variant has been reported to have incomplete penetrance as there are unaffected carriers of this variant (PMID: 28350801; gnomAD). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable ages of onset and differences in disease progression have been reported (PMID: 24650794; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (25 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Ala713Val): 13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). The amino acid residue is also a gamma-secretase cleavage site (UniProt). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Ala713Val) has been described as ‘not pathogenic’ in the literature, with no increase in the ABeta42/40 ratio or ABeta42 demonstrated for this variant (PMIDs: 32087291, 31011484). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with mild cognitive impairment, progressive dementia and Alzheimer disease including several large families with Alzheimer disease (PMIDs: 15488330, 15365148, 23143229, 25948718, 28350801, 32908482). It should be noted that this variant was recently classified as a risk factor; however limited justification was provided for the classification (PMID: 32087291). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Injection of human brain extracts from a deceased individual carrying the p.(Ala713Thr) variant into mice resulted in brain amyloidosis with higher ABeta levels detected in the insoluble faction of brain homogenates compared to control mice (PMID: 29459625). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

While the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, it is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org, PMID: 1303275, 19363265, 26803359, 29859640, 30279455, 32917274). This variant has been identified in at least one individual with clinical features associated with this gene. This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 29459625, 32087291)