Proteinuric renal disease

Gene: APOE

Green List (high evidence)

Comment on mode of inheritance: There are numerous patients with proteinuria and glomerulopathy linked to APOE variants. However, most of these patients harbour monoallelic rare variants, together with a homozygous APOE2 risk allele. There seems to be only 1 case reported with biallelic rare APOE missense variants, inherited from unaffected parents (PMID: 35119017). Hence, the mode of inheritance should stay MONOALLELIC, until more evidence emerges.

Created: 9 Sep 2026, 10:34 a.m. | Last Modified: 9 Sep 2026, 10:34 a.m.

Panel Version: 6.18

PMID: 24570682 Kawanishi et al., 2013
Report of 3 likely Japanese cases of APOE homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 patients were homozygous for APOE p.Arg158Cys variant - NM_000041.4: c.526C>T, p.Arg176Cys - common variant, B/LB in ClinVar. Risk factor.
Case 1 - 66yo male, diagnosed with diabetes at 50 yrs, untreated; testing showed urinary abnormality of protein 3+ (urinary protein 2.07g/day) and occult blood 1+, serum creatinine level of 0.96 mg/dl; on renal biopsy, 1/11 glomeruli showed global sclerosis, and the other glomeruli showed massive foam cell infiltration in the glomerular capillaries and mildly expanded mesangium.

Case 2 - 58yo male with nephrotic syndrome; urinary protein 7.38 g/day, hypoalbuminemia (1.9 g/dl); he was treated for diabetes since the age of 50 years; renal biopsy revealed 5 of 22 glomeruli with global sclerosis; residual glomeruli showed massive foam cell infiltration in the glomerular capillaries and severely widened mesangium - foam cells stained positive for CD68.

Case 3 - 78yo male with nephrotic syndrome; medical history includes hypertension, hypothyroidism, and diabetes mellitus; urinary protein 2.5 g/day, red blood cells in urine (1–4/hpf). A kidney biopsy revealed 21 glomeruli, of which 2 were globally sclerotic. The glomeruli showed increased mesangial matrices and mild GBM thickening. Massive foam cells had infiltrated into the glomerular capillaries and mesangial region.

PMID: 29692990 Fukunaga et al., 2018
Report of a Japanese 20yo female with proteinuria (3+) and hematuria (3+); on renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change; diagnosed with membranous nephropathy. She was homozygous for APOE2 allele and heterozygous for APOE p.Ser197Cys rare variant - NM_000041.4: c.644C>G, p.Ser215Cys (not in gnomAD 4.1.1).

PMID: 35119017 Li et al., 2021
Report of a 28-year-old man who presented with severe proteinuria (4+), hyperlipidemia (serum total cholesterol, 7.09 mmol/L, low-density lipoprotein cholesterol [LDL-C], 6.39 mmol/L), edema of both legs, and normal serum albumin level; he was diagnosed with lipoprotein glomerulopathy. Renal biopsy revealed lipoprotein thrombi in the glomeruli. Immunofluorescence staining revealed APOE-positive deposits, particularly within the glomeruli. He was comp het for APOE variants: c.127C > T (p.Arg43Cys) & c.149G > A (p.Arg50His) - in trans, inherited from unaffected het parents. Both variants are rare in gnomAD, with no homozygotes reported.

PMID: 35950048 Koshino et al., 2022
Case report: 28-year-old Japanese man with mild proteinuria (+1) and hematuria, harbouring het APOE variant p.(Ser197Cys) and homozygous apoE2/2 risk allele. Kidney biopsy revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion; EM showed massive deposits with various electron densities, the glomerular basement membrane (GBM) structure was partly degenerated by these deposits.

Created: 9 Sep 2026, 10:06 a.m. | Last Modified: 9 Sep 2026, 10:25 a.m.

Panel Version: 6.18

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Lipoprotein glomerulopathy, OMIM:611771; lipoprotein glomerulopathy, MONDO:0012725

Publications

• 24570682
• 29692990

Comment on list classification: Changed rating to Amber to reflect NHS signed-off rating, will be examined at next panel review.

Created: 16 Oct 2020, 8:04 a.m. | Last Modified: 16 Oct 2020, 8:04 a.m.

Panel Version: 2.28

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 7 Mar 2022, 11:37 p.m. | Last Modified: 7 Mar 2022, 11:37 p.m.

Panel Version: 2.66

Set Penetrance to incomplete as several reports of unaffected individuals who carry the same variants as affected individuals.

Created: 30 Mar 2020, 7:53 p.m. | Last Modified: 30 Mar 2020, 7:53 p.m.

Panel Version: 2.19

Comment on list classification: Changing rating from grey to green as many published cases of variants in APOE in patients with Lipoprotein glomerulopathy

Created: 30 Mar 2020, 7:50 p.m. | Last Modified: 30 Mar 2020, 7:50 p.m.

Panel Version: 2.17

Associated with Lipoprotein glomerulopathy #611771 in OMIM. No inheritance pattern listed.

Several publications report variants in the APOE gene in association with Lipoprotein glomerulopathy, mostly in individuals of Asian ethnicity but also in those with European ancestry (for example PMID: 18077821 - Rovin et al 2007). PMID: 31092271 - Xie et al 2019 lists many of the published variants (~12 to date, mostly point mutations, but also some deletions)

In several cases clinical asymptomatic carriers (all female?) also carry the same variants as probands e.g.
PMID: 18077821 - Rovin et al 2007
PMID: 10432380 - Matsunaga et al 1999
PMID: 31092271 - Xie et al 2019

Created: 30 Mar 2020, 5:17 p.m. | Last Modified: 30 Mar 2020, 7:49 p.m.

Panel Version: 2.16

Green List (high evidence)

Specific variants in Japanese/Chinese linked to the development of a glomerulopathy, characterised by proteinuria, renal failure and deposition of lipoprotein thrombi.
Sources: Expert list

Created: 9 Jan 2020, 3:22 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Lipoprotein glomerulopathy, MIM# 611771

Publications

• 10432380
• 9176854
• 18077821