Submissions for variant NM_003661.4(APOL1):c.1024A>G (p.Ser342Gly)

gnomAD frequency: 0.06773  dbSNP: rs73885319

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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]
Invitae	RCV001374176	SCV001570962	uncertain significance	not provided	2022-10-26	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 several forms of 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 at Invitae. ClinVar contains an entry for this variant (Variation ID: 277678). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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, its significance when present in heterozygosity is unclear. For these reasons, this change has been classified as a Variant of Uncertain Significance.
GeneDx	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)
Mendelics	RCV002248501	SCV002516948	likely risk allele	not specified	2023-02-15	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	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).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003826	SCV001162277	pathogenic	Proteinuria		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003827	SCV001162278	pathogenic	Focal segmental glomerulosclerosis		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003828	SCV001162279	pathogenic	Focal segmental glomerulosclerosis; Sickled erythrocytes		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003829	SCV001162280	pathogenic	Focal segmental glomerulosclerosis; Steroid-resistant nephrotic syndrome		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003830	SCV001162281	pathogenic	Nephrotic range proteinuria		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003831	SCV001162282	pathogenic	Glomerulonephritis		no assertion criteria provided	research