ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.1481del (p.Ser494fs)

gnomAD frequency: 0.00001  dbSNP: rs386833883
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000804539 SCV000944453 pathogenic not provided 2023-08-17 criteria provided, single submitter clinical testing This variant is present in population databases (rs386833883, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Ser494Cysfs*55) 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 premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 10577936, 18614772). ClinVar contains an entry for this variant (Variation ID: 56441). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049854 SCV001983583 pathogenic Finnish congenital nephrotic syndrome 2021-09-03 criteria provided, single submitter clinical testing Variant summary: NPHS1 c.1481delC (p.Ser494CysfsX55) 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 4.7e-06 in 212490 control chromosomes. c.1481delC has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (e.g. Bolk_1999). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000804539 SCV002588243 pathogenic not provided 2022-04-29 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31028937, 10577936, 18614772)
Baylor Genetics RCV000049854 SCV004191433 pathogenic Finnish congenital nephrotic syndrome 2024-02-22 criteria provided, single submitter clinical testing
OMIM RCV000049854 SCV000027469 pathogenic Finnish congenital nephrotic syndrome 1999-12-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049854 SCV000082263 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049854 SCV002087084 pathogenic Finnish congenital nephrotic syndrome 2021-10-10 no assertion criteria provided clinical testing

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