Submissions for variant NM_000484.4(APP):c.982C>T (p.Arg328Trp)

gnomAD frequency: 0.00019  dbSNP: rs200978018

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001138973	SCV001299070	uncertain significance	Alzheimer disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824924	SCV002074516	uncertain significance	not specified	2022-01-04	criteria provided, single submitter	clinical testing	Variant summary: APP c.982C>T (p.Arg328Trp) results in a non-conservative amino acid change located in the Pancreatic trypsin inhibitor Kunitz domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251186 control chromosomes. c.982C>T has been reported in the literature in individuals affected with Alzheimer Disease (Liddell_1995, Perrone_2020) and a dementia patient with sporadic inclusion body myositis (Weihl_2015), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Alzheimer Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001138973	SCV002304304	likely benign	Alzheimer disease	2024-01-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001356009	SCV002504207	likely benign	not provided	2019-09-30	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356009	SCV001551056	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APP p.R328W variant was not identified in the literature but was identified in dbSNP (ID: rs200978018) and ClinVar (classified as uncertain significance by Illumina). The variant was identified in control databases in 48 of 282564 chromosomes at a frequency of 0.0001699, and was observed at the highest frequency in the European (non-Finnish) population in 43 of 129002 chromosomes (freq: 0.0003333) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R328 residue is conserved in mammals and more distantly related organisms however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.