rs429358
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBA1
The NM_000041.4(APOE):c.388T>C(p.Cys130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,567,892 control chromosomes in the GnomAD database, including 17,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars).
Frequency
Consequence
NM_000041.4 missense
Scores
Clinical Significance
Conservation
Publications
- Alzheimer disease 2Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- hyperlipoproteinemia type 3Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
- lipoprotein glomerulopathyInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
- sea-blue histiocyte syndromeInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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APOE | NM_000041.4 | c.388T>C | p.Cys130Arg | missense_variant | Exon 4 of 4 | ENST00000252486.9 | NP_000032.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOE | ENST00000252486.9 | c.388T>C | p.Cys130Arg | missense_variant | Exon 4 of 4 | 1 | NM_000041.4 | ENSP00000252486.3 | ||
APOE | ENST00000425718.1 | c.388T>C | p.Cys130Arg | missense_variant | Exon 3 of 3 | 1 | ENSP00000410423.1 | |||
APOE | ENST00000434152.5 | c.466T>C | p.Cys156Arg | missense_variant | Exon 4 of 4 | 2 | ENSP00000413653.2 | |||
APOE | ENST00000446996.5 | c.388T>C | p.Cys130Arg | missense_variant | Exon 4 of 4 | 2 | ENSP00000413135.1 |
Frequencies
GnomAD3 genomes AF: 0.157 AC: 23875AN: 151972Hom.: 1998 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.138 AC: 23502AN: 169692 AF XY: 0.136 show subpopulations
GnomAD4 exome AF: 0.148 AC: 208931AN: 1415800Hom.: 15700 Cov.: 34 AF XY: 0.146 AC XY: 102105AN XY: 700502 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.157 AC: 23933AN: 152092Hom.: 2010 Cov.: 32 AF XY: 0.161 AC XY: 11948AN XY: 74354 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Other:2
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No Rules Apply -
- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
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Alzheimer disease 2 Pathogenic:2
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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. -
Alzheimer disease Pathogenic:2
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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. -
Alzheimer disease 4 Pathogenic:1
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM4. This variant was detected in homozygous state. -
Lipoprotein glomerulopathy Uncertain:1
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not specified Benign:1
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Warfarin response Other:1
- likely responsive
Primary degenerative dementia of the Alzheimer type, presenile onset Other:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at