Submissions for variant NM_003661.4(APOL1):c.1164_1169del (p.Asn388_Tyr389del)

dbSNP: rs71785313

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000006454	SCV000924397	risk factor	Focal segmental glomerulosclerosis 4, susceptibility to	2015-02-27	criteria provided, single submitter	clinical testing	G2
Invitae	RCV001295848	SCV001484798	uncertain significance	not provided	2024-01-25	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 several forms of 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 protein 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, its significance when present in heterozygosity is unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001295848	SCV001859790	benign	not provided	2019-02-07	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
OMIM	RCV000006454	SCV000026637	risk factor	Focal segmental glomerulosclerosis 4, susceptibility to	2010-08-13	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003838	SCV001162289	pathogenic	Focal segmental glomerulosclerosis		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003839	SCV001162290	pathogenic	Nephrotic range proteinuria		no assertion criteria provided	research