NM_000041.4:c.526C>T
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_StrongBA1
The NM_000041.4(APOE):c.526C>T(p.Arg176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,540,810 control chromosomes in the GnomAD database, including 4,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).
Frequency
Consequence
NM_000041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOE | NM_000041.4 | c.526C>T | p.Arg176Cys | 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.526C>T | p.Arg176Cys | missense_variant | Exon 4 of 4 | 1 | NM_000041.4 | ENSP00000252486.3 | ||
APOE | ENST00000425718.1 | c.526C>T | p.Arg176Cys | missense_variant | Exon 3 of 3 | 1 | ENSP00000410423.1 | |||
APOE | ENST00000434152.5 | c.604C>T | p.Arg202Cys | missense_variant | Exon 4 of 4 | 2 | ENSP00000413653.2 | |||
APOE | ENST00000446996.5 | c.526C>T | p.Arg176Cys | missense_variant | Exon 4 of 4 | 2 | ENSP00000413135.1 |
Frequencies
GnomAD3 genomes AF: 0.0779 AC: 11838AN: 152004Hom.: 546 Cov.: 32
GnomAD3 exomes AF: 0.0615 AC: 8425AN: 136984Hom.: 315 AF XY: 0.0613 AC XY: 4615AN XY: 75288
GnomAD4 exome AF: 0.0738 AC: 102550AN: 1388698Hom.: 4063 Cov.: 34 AF XY: 0.0726 AC XY: 49779AN XY: 685974
GnomAD4 genome AF: 0.0778 AC: 11840AN: 152112Hom.: 546 Cov.: 32 AF XY: 0.0745 AC XY: 5538AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2Other:2
The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. -
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- 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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APOE: PM5, BS1, BS2 -
Familial type 3 hyperlipoproteinemia Pathogenic:1
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not specified Benign:1
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Hypercholesterolemia Benign:1
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atorvastatin response - Efficacy Other:1
PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy
Warfarin response Other:1
- likely responsive
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at