Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001386879 | SCV001587274 | pathogenic | Alzheimer disease | 2020-06-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid with glutamine at codon 693 of the APP protein (p.Glu693Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary cerebral amyloid angiopathy and in individual(s) with Alzheimer's disease (PMID: 2111584, 23919771, 11004129). This variant has also been shown to segregate with disease. This variant is also known as p.Glu22Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 18087). This variant has been reported to affect APP protein function (PMID: 19061884, 11441013, 10821838, 8610157). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002272024 | SCV002557984 | pathogenic | Cerebral amyloid angiopathy, APP-related | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Toxic gain of function is a known mechanism of disease in this gene and is associated with Alzheimer disease 1, familial (MIM#104300) (PMID: 24524897). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. p.(Ala713Thr) has been reported to exhibit reduced penetrance (PMID: 28350801). (I) 0115 - Variants in this gene are known to have variable expressivity. Age of onset and disease progression can vary (GeneReviews; PMID: 24650794). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 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). (SP) 0703 – Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change to a lysine has been reported in one individual with hereditary cerebral amyloid angiopathy and also in another individual with early onset Alzheimer disease (ClinVar, PMID: 10821838, 28350801). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported Dutch variant, HCHWA-D, and has been reported in multiple individuals with hereditary cerebral amyloid angiopathy and in individuals with Alzheimer's disease (ClinVar, PMID: 2111584, 10821838, 19061884, 23919771, 30868685). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000019713 | SCV000040011 | pathogenic | ABeta amyloidosis, dutch type | 2000-09-01 | no assertion criteria provided | literature only |