ClinVar Miner

Submissions for variant NM_014625.3(NPHS2):c.686G>A (p.Arg229Gln) (rs61747728)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157404 SCV000207143 uncertain significance Proteinuria 2015-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000576535 SCV000677983 likely pathogenic Nephrotic syndrome, idiopathic, steroid-resistant 2016-07-27 criteria provided, single submitter clinical testing The pathogenicity of R229Q is dependent on the variant observed on the other chromosome. In homozygous state, R229Q is not disease-causing.
Integrated Genetics/Laboratory Corporation of America RCV000855599 SCV000699384 uncertain significance not specified 2019-01-24 criteria provided, single submitter clinical testing Variant summary: NPHS2 c.686G>A (p.Arg229Gln) results in a conservative amino acid change located in the Band 7 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.031 in 279212 control chromosomes in the gnomAD database and publications, including 190 homozygotes. The observed variant frequency is approximately 17.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS2 causing Nephrotic Syndrome, Type 2 phenotype (0.0018), suggesting that the variant is benign. However, c.686G>A has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 but also in unaffected individuals (Benetti_2014, Guaragna_2015, Hinkes_2007, Kerti_2013, Machuca_2009, McCarthy_2013, Zhang_2004). The Arg229Gln substitution has been extensively studied and was observed in multiple affected individuals as homozygous, compound heterozygous, and co-occurrences with another pathogenic variant(s), along with being observed in a homozygous state in unaffected individuals. The variant of interest has been shown to have reduced penetrance, along with variable expressivity. An extensive study performed by Tory_2014, concluded that the pathogenicity of R229Q is highly dependent on the NPHS2 variant observed in trans. The c.686G>A in trans with certain variants located in exons 7 and 8 such as Ala284, Ala288, Arg291, Ala297, Glu310, Leu327 or Gln328 have a deleterious effect due to altered heterodimerization and mislocalization of the encoded p.Arg229Gln podocin causing a dominant-negative effect. However, variants located in exons 1-6 in trans with R299Q are less likely to be deleterious. Multiple publications have classified the variant as a "non-neutral polymorphism." Association studies have provided conflicting results with association to risk, however, the majority of these associations did not specifically look at genotype (i.e. compound heterozygous with trans variant in exons 1-6 vs. exons 7-8) to assess risk. Miko et al. (2018) concluded in their review that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:106). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity in ability of mutant NPHS2 (p.Arg299Gln mutant Podocin) to bind to Nephrin (NPHS1)(Tsukaguchi_2002). Four ClinVar submissions from clinical diagnostic laboratories and a research laboratory (evaluation after 2014) cite the variant as pathogenic (2x), likely pathogenic (1x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Athena Diagnostics Inc RCV000590501 SCV000842933 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
OMIM RCV000005701 SCV000025883 risk factor Nephrotic syndrome, type 2, susceptibility to 2014-03-01 no assertion criteria provided literature only
Gharavi Laboratory,Columbia University RCV000590501 SCV000809410 pathogenic not provided 2018-09-16 no assertion criteria provided research

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