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
Athena Diagnostics Inc RCV000590501 SCV000842933 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing
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.
Gharavi Laboratory,Columbia University RCV000590501 SCV000809410 pathogenic not provided 2018-09-16 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000590501 SCV000699384 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing Variant summary: The NPHS2 c.686G>A (p.Arg229Gln) variant causes a missense change involving a conserved nucleotide located in exon 5 (Band 7 domain) with 3/3 in silico tools predicting "benign" outcome. The variant of interest was observed in controls with an allele frequency of 3628/121678 control chromosomes (69 homozygotes, 1/33), which exceeds the estimated maximal expected allele frequency for a pathogenic NPHS2 variant of 1/565. Nephrotic syndrome is a genetically heterogenous disease with more than 20 genes being identified in monogenic forms, most of which encode podocyte proteins (Tory_2014). 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 (ie, compound heterozygous with trans variant in exons 1-6 vs. exons 7-8) to assess risk. Therefore, due to the complexity of this variant, it has been classified as a "Variant of Uncertain Significance (VUS)," however, it needs to be noted that a variant in trans located within exons 1-6 would most likely classify the variant of interest in the benign spectrum, where as a variant in trans located in exons 7-8 would most likely be classified in the pathogenic spectrum.
OMIM RCV000005701 SCV000025883 risk factor Nephrotic syndrome, type 2, susceptibility to 2014-03-01 no assertion criteria provided literature only

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