Submissions for variant NM_000041.4(APOE):c.388T>C (p.Cys130Arg)

gnomAD frequency: 0.16059  dbSNP: rs429358

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000292119	SCV000333415	other	not provided	2017-11-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826089	SCV000967586	risk factor	Primary degenerative dementia of the Alzheimer type, presenile onset	2019-01-16	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000292119	SCV000987489	risk factor	not provided		criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000991302	SCV001142704	likely pathogenic	Alzheimer disease	2019-06-27	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001195807	SCV001366227	pathogenic	Alzheimer disease 4	2020-03-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM4. This variant was detected in homozygous state.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262791	SCV001440792	uncertain significance	Lipoprotein glomerulopathy	2019-01-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000292119	SCV002502503	likely pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000292119	SCV002822580	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing
OMIM	RCV000019448	SCV000039738	pathogenic	Alzheimer disease 2	2022-06-27	no assertion criteria provided	literature only
Pharmacogenomics Lab, Chungbuk National University	RCV000845581	SCV000889946	drug response	Warfarin response	2010-08-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000019448	SCV001550609	established risk allele	Alzheimer disease 2		no assertion criteria provided	clinical testing	The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 deleterious effect on 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. However, this variant may act as a risk factor for Alzheimer's Disease.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000991302	SCV002764628	established risk allele	Alzheimer disease		no assertion criteria provided	research	The variant APOE c.388T>C (p.Cys130Arg) was identified in dsSNP (ID: rs429358) and Clinvar (classified as pathogenic by OMIM). Farrer et al. reported in a meta-analysis (5930 patients who met the criteria for Alzheimer disease (AD), and 8607 controls) that the p.Cys130Arg variant (also known as the e4 variant) represented a major risk factor for AD, with the risk of AD significantly increased among Caucasian subjects with genotypes e2/e4 (OR=2.6, 95% CI=1.6-4.0), e3/e4 (OR=3.2, 95% CI=2.8-3.8), and e4/e4 (OR=14.9, 95% CI 10.8-20.6). The association between p.Cys130Arg and AD was stronger in Japanese subjects with genotypes e3/e4 (OR=5.6, 95% CI 3.0-8.0) and e4/e4 (OR=33.1, 95% CI=13.6-80.5) (Farrer_1997_9343467). Another study using data from 1968 African American patients with Late-Onset Alzheimer Disease (LOAD) and 3928 control patients showed that SNPs such as p.Cys130Arg in the APOE region were significant for association with LOAD (P = 5.5 × 10–47) (Reitz_2013_ 23571587). In addition, another study involving 45 patients with AD and 53 controls of Ashkenazi Jewish ancestry observed an association signal for AD risk for the variant p.Cys130Arg (P =1.02×E−08, OR=0.6, 95% CI: 4.20–26.8) (Freudenberg-Hua_2016_27260402). In vivo and in vitro functional studies also provide evidence that the p.Cys130Arg variant may have an effect on increased amyloid beta accumulation, neurotoxicity, and neuritic dystrophy (Youmans_2012_23060451, Liu_2014_29216449). The variant was identified in control databases in 28,637 of 200,920 chromosomes (2,091 homozygous) at a frequency of 14.2529%, and was observed at the highest frequency in the European-Non Finnish (NFE) population in 12,460 of 83,842 chromosomes (freq: 14.8613%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Cys130Arg residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 deleterious effect on 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. However, this variant may act as a risk factor for Alzheimer's Disease.