ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.1379G>A (p.Arg460Gln) (rs386833880)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049851 SCV000220658 likely pathogenic Finnish congenital nephrotic syndrome 2014-08-29 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000049851 SCV000915829 pathogenic Finnish congenital nephrotic syndrome 2017-07-20 criteria provided, single submitter clinical testing Across a selection of the available literature, the NPHS1 c.1379G>A (p.Arg460Gln) variant has been identified in at least 11 individuals with congenital Finnish nephrosis. Specifically, the p.Arg460Gln variant was reported in a homozygous state in six individuals, in a compound heterozygous state in three individuals, and in a heterozygous state in two individuals (Sako et al. 2005; Heeringa et al. 2008; Lee et al. 2009; Machuca et al. 2010; Schoeb et al. 2010). The p.Arg460Gln variant was also found in a heterozygous state in the unaffected mother of an affected heterozygote (Sako et al. 2005). Two of the compound heterozygotes have null variants on the second allele (Heeringa et al. 2008; Machuca et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000183 in the Other population of the Genome Aggregation Database but this is based on one allele so the variant is presumed to be rare. Based on the evidence, the p.Arg460Gln variant is classified as pathogenic for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000049851 SCV000917904 pathogenic Finnish congenital nephrotic syndrome 2017-09-14 criteria provided, single submitter clinical testing Variant summary: The NPHS1 c.1379G>A (p.Arg460Gln) variant located in the Immunoglobulin-like fold domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/215308 control chromosomes at a frequency of 0.0000093, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Multiple publications have cited the variant in homozygous and compound heterozygous affected pts. A functional study, Philippe_2008 indicates that the variant was shown to traffic normally in the cell and to homodimerize and to heterodimerize with NEPH1, but they suggest that additional studies are needed to evaluate whether missense variants that traffic to the membrane affect nephrin phosphorylation, actin reorganization in the cytoskeleton of podocytes, or downstream signaling events involved in transcriptional regulation and apoptosis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049851 SCV000082260 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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