Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Variantyx, |
RCV000006454 | SCV007448764 | pathogenic | Focal segmental glomerulosclerosis 4, susceptibility to | 2025-03-27 | criteria provided, single submitter | clinical testing | This is an in-frame deletion variant in the APOL1 gene (OMIM: 603743). Pathogenic variants in this gene have been associated with autosomal recessive susceptibility to segmental glomerulosclerosis 4. This variant causes an in-frame deletion of two amino acids at position 388 of the APOL1 protein (PM4). This variant is typically referred to as the G2 allele and is common in individuals of African ancestry. Homozygosity or compound heterozygosity of this variant with the G1 allele (p.[Ser342Gly;Ile384Met]) have been associated with an increased increased risk for chronic kidney disease, including focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN). Equivalent risk associations have been observed for the G1/G1, G1/G2 and G2/G2 genotypes, with the strongest effect across studies detected for HIVAN (OR=29, 95% CI 13-68.5), followed by FSGS (OR=17, 95% CI 11-26) (PMID: 21997394, 24206458, 24379297, 25853332, 25168832) (PS4). Functional studies have shown that this variant alters APOL1 protein function (PMID: 28218918, 28650456) (PS3). This variant has a 14% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic with low penetrance for autosomal recessive susceptibility to segmental glomerulosclerosis 4. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004585990 | SCV005077605 | likely benign | not specified | 2024-04-29 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000006454 | SCV002518488 | likely risk allele | Focal segmental glomerulosclerosis 4, susceptibility to | 2023-03-24 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001295848 | SCV001859790 | benign | not provided | 2019-02-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001295848 | SCV001484798 | pathogenic, low penetrance | not provided | 2026-02-01 | criteria provided, single submitter | clinical testing | This variant, c.1164_1169del, results in the deletion of 2 amino acid(s) of the APOL1 protein (p.Asn388_Tyr389del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs143830837, gnomAD 14%), and has an allele count higher than expected for a pathogenic variant. This variant constitutes the “G2” allele of APOL1. This allele is associated with increased risk for progressive proteinuric nephropathy and kidney disease in individuals of African-American ancestry when present in homozygosity or in trans with the “G1” allele (which is composed of the c.1024A>G (p.Ser342Gly) and c.1152T>G (p.Ile384Met) variants in cis). Several large case-control studies have shown a 6- to 47-fold increased risk of focal segmental glomerulosclerosis, HIV-associated nephropathy, or non-diabetic end-stage kidney disease in individuals with homozygous G1, homozygous G2, or G1 in trans with G2 alleles (PMID: 20647424, 20635188, 21997394). Similar studies in African populations have generally recapitulated these findings, but these studies are based on a relatively small number of individuals (PMID: 30340464, 25788523). A recent PheWAS study also appears to support these findings, although the risk of end-stage kidney disease may be smaller than initially assumed (closer to 3- to 4-fold; PMID: 32247630). ClinVar contains an entry for this variant (Variation ID: 6081). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APOL1 function (PMID: 30332315, 32675303). In summary, this variant has been shown to confer an increased risk for kidney disease, either in homozygosity or in trans with the G1 allele. However, not all individuals with this variant in homozygosity or in trans with the G1 allele will be clinically affected. For these reasons, this change has been classified as Pathogenic (low penetrance). |
| Molecular Diagnostics Lab, |
RCV000006454 | SCV000924397 | risk factor | Focal segmental glomerulosclerosis 4, susceptibility to | 2015-02-27 | criteria provided, single submitter | clinical testing | G2 |
| Laboratory for Molecular Medicine, |
RCV001195105 | SCV000197066 | risk factor | Hyalinosis, Segmental Glomerular | 2020-03-04 | criteria provided, single submitter | clinical testing | APOL1 c.1164_1169del (p.Asn388_Tyr389del), traditionally referred to as G1, has been associated with increased risk for multiple renal diseases in African Americans, particularly focal segmental glomerulosclerosis (FSGS), as well as an increased risk for end-stage kidney disease (ESKD). This variant is common in individuals of African ancestry (14%, Genome Aggregation Database (gnomAD); rs71785313) and is present in ClinVar (ID: 6081). Several small case-control studies have reported odds ratios between 3.92-25.1 for developing FSGS/HIVAN in homozygous individuals (OR=3.92 [95% CI 1.47-9.39] for FSGS/HIVAN Ito 2014, OR=14.4 [95% CI 1.7-116.3] for HIVAN, OR=25.1 [95% CI 8.8-83.3] for FSGS Kopp 2011, OR=5.69 [95% CI not given, P<0.00001] Limou 2015). In vitro and in vivo studies provide some evidence that these alleles impact protein function (Beckerman 2017, Hayek 2017). In summary, this variant is an established risk factor for chronic kidney disease in homozygous state. |
| NIHR Bioresource Rare Diseases, |
RCV001003839 | SCV001162290 | pathogenic | Nephrotic range proteinuria | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003838 | SCV001162289 | pathogenic | Focal segmental glomerulosclerosis | no assertion criteria provided | research | ||
| OMIM | RCV000006454 | SCV000026637 | risk factor | Focal segmental glomerulosclerosis 4, susceptibility to | 2010-08-13 | no assertion criteria provided | literature only |