ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.1379G>A (p.Arg460Gln)

gnomAD frequency: 0.00002  dbSNP: rs386833880
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
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 Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV001388275 SCV001589205 pathogenic not provided 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 460 of the NPHS1 protein (p.Arg460Gln). This variant is present in population databases (rs386833880, gnomAD 0.003%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 19194555, 21125408, 21415313, 30655312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56438). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion RCV000049851 SCV002059163 pathogenic Finnish congenital nephrotic syndrome 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000056438, PMID:11317351, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 30655312, 21125408, 19194555, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002294008 SCV002587197 likely pathogenic Kidney disorder 2016-12-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000049851 SCV002781746 pathogenic Finnish congenital nephrotic syndrome 2021-07-21 criteria provided, single submitter clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000049851 SCV004024494 pathogenic Finnish congenital nephrotic syndrome 2023-07-01 criteria provided, single submitter research
Vasylyeva lab, Texas Tech University Health Sciences Center RCV000049851 SCV004123152 pathogenic Finnish congenital nephrotic syndrome 2022-01-03 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001388275 SCV004145519 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing NPHS1: PM3:Very Strong, PM2, PS4:Moderate, PS3:Supporting, BP4
Baylor Genetics RCV000049851 SCV004191378 pathogenic Finnish congenital nephrotic syndrome 2023-10-20 criteria provided, single submitter clinical testing
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.
Natera, Inc. RCV000049851 SCV001460540 pathogenic Finnish congenital nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing
Yale Center for Mendelian Genomics, Yale University RCV001849302 SCV002106846 likely pathogenic Nephrotic syndrome 2017-11-10 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.