Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Dasa | RCV001374176 | SCV007599746 | pathogenic | not provided | 2026-01-19 | criteria provided, single submitter | clinical testing | NM_003661.4(APOL1):c.1024A>G (p.Ser342Gly) is a missense variant that results in the substitution of serine with glycine. This variant has been recurrently observed in individuals with related phenotype (PMID: 27600725; PMID: 27610422; PMID: 40321250). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Variantyx, |
RCV005355580 | SCV007294374 | pathogenic | Focal segmental glomerulosclerosis 4, susceptibility to | 2025-03-25 | criteria provided, single submitter | clinical testing | This is a complex allele formed by two nonsynonymous variants in the APOL1 gene (OMIM: 603743). Pathogenic variants in this gene have been associated with autosomal recessive susceptibility to segmental glomerulosclerosis 4. This haplotype is traditionally referred to as the G1 allele and is common in individuals of African ancestry. Homozygosity or compound heterozygosity of this variant with the G2 allele (p.Asn388_Tyr389del) have been associated with an 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 allele alters APOL1 protein function (PMID: 28218918, 28650456) (PS3). This allele has a maximum allele frequency of approximately 23% in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this allele is classified as pathogenic with low penetrance for autosomal recessive susceptibility to segmental glomerulosclerosis 4.The APOL1 G2 allele was also identified in this individual. |
| Department of Pathology and Laboratory Medicine, |
RCV005355580 | SCV005913586 | likely pathogenic | Focal segmental glomerulosclerosis 4, susceptibility to | 2023-09-15 | criteria provided, single submitter | research | |
| Clinical Genomics Laboratory, |
RCV003458390 | SCV004176970 | uncertain significance | APOL1-associated kidney disease | 2023-08-29 | criteria provided, single submitter | clinical testing | Sequence analysis identified the presence of a single APOL1 risk allele in a heterozygous state (G1). The G1 allele is composed of two missense variants: G1G (p.S342G) and G1M (p.I384M). APOL1 risk alleles occur at high frequency among populations of African ancestry (22-24% and 13-14% for G1 and G2, respectively) and are absent or nearly absent from other populations. Inheriting two risk variants greatly increases risk of kidney disease, whereas inheriting one risk allele confers minimal or no risk (Friedman DJ et al., PMID: 32616495). APOL1-associated kidney disease includes focal segmental glomerulosclerosis, CKD associated with hypertension, HIV, systemic lupus erythematosus (SLE), and sickle cell disease, among others (Friedman DJ et al., PMID: 32616495). |
| Mendelics | RCV002248501 | SCV002516948 | likely risk allele | not specified | 2023-02-15 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001374176 | SCV001936051 | risk factor | not provided | 2020-02-26 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 28696248, 27650483, 32581362, 21910715, 24379297, 23768513, 24518129, 25993319, 22832513, 24206458, 20635188, 20647424, 30173819, 30315176) |
| Labcorp Genetics |
RCV001374176 | SCV001570962 | pathogenic, low penetrance | not provided | 2026-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 342 of the APOL1 protein (p.Ser342Gly). This variant is present in population databases (rs73885319, gnomAD 23%), and has an allele count higher than expected for a pathogenic variant. This variant, along with c.1152T>G (p.Ile384Met), constitutes the “G1” 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 “G2” allele (c.1164_1169delTTATAA (p.Asn388_Tyr389del)). 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). p.Ile384Met and p.Ser342Gly are almost always present on the same allele (in cis), but p.Ser342Gly is thought to be the main driver of increased risk (PMID: 21997394). p.Ile384Met is therefore classified as Benign (internal data). ClinVar contains an entry for this variant (Variation ID: 277678). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects 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 G2 allele. However, not all individuals with this variant in homozygosity or in trans with the G2 allele will be clinically affected. For these reasons, this change has been classified as Pathogenic (low penetrance). |
| Laboratory for Molecular Medicine, |
RCV000408955 | SCV000204327 | risk factor | Hyalinosis, Segmental Glomerular | 2020-03-04 | criteria provided, single submitter | clinical testing | See compound het c.[1024A>G;1152T>G] |
| NIHR Bioresource Rare Diseases, |
RCV001003831 | SCV001162282 | pathogenic | Glomerulonephritis | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003830 | SCV001162281 | pathogenic | Nephrotic range proteinuria | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003829 | SCV001162280 | pathogenic | Focal segmental glomerulosclerosis; Steroid-resistant nephrotic syndrome | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003828 | SCV001162279 | pathogenic | Focal segmental glomerulosclerosis; Sickled erythrocytes | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003827 | SCV001162278 | pathogenic | Focal segmental glomerulosclerosis | no assertion criteria provided | research | ||
| NIHR Bioresource Rare Diseases, |
RCV001003826 | SCV001162277 | pathogenic | Proteinuria | no assertion criteria provided | research |