ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.2596C>T (p.Arg866Ter)

gnomAD frequency: 0.00001  dbSNP: rs386833920
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049894 SCV000486707 likely pathogenic Finnish congenital nephrotic syndrome 2016-07-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001388273 SCV001589202 pathogenic not provided 2024-02-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg866*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs386833920, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with congenital nephrotic syndrome (PMID: 18503012). ClinVar contains an entry for this variant (Variation ID: 56481). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049894 SCV001821229 pathogenic Finnish congenital nephrotic syndrome 2021-08-12 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.2596C>T (p.Arg866X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 245462 control chromosomes. c.2596C>T has been reported in the literature in at-least one individual affected with Nephrotic Syndrome, Type 1 and has been subsequently cited by others (example, Heeringa_2008, Lovric_2014, Sadowski_2015, Machuca_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251954 SCV002523896 likely pathogenic See cases 2020-12-15 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PS4, PM2
Baylor Genetics RCV000049894 SCV004191467 pathogenic Finnish congenital nephrotic syndrome 2023-03-22 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049894 SCV000082303 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328088 SCV001449380 pathogenic Nephrotic syndrome 2018-09-05 no assertion criteria provided clinical testing This patient is heterozygous for a known pathogenic variant, c.2596C>T, in the NPHS1 gene. This variant (dbSNP: rs386833920) creates a premature stop codon (p.Arg866*), and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been previously reported in a compound heterozygote with another pathogenic NPHS1 variant in a two month old child with congenital nephrotic syndrome (Heeringa et al 2008 Nephrol Dial Transplant 23:3527-3533). This variant is considered to be a pathogenic according to the ACMG guidelines
Natera, Inc. RCV000049894 SCV002087079 pathogenic Finnish congenital nephrotic syndrome 2021-07-22 no assertion criteria provided clinical testing

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