ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.1019C>A (p.Pro340His)

gnomAD frequency: 0.00001  dbSNP: rs386833861
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000049830 SCV001164372 uncertain significance Finnish congenital nephrotic syndrome 2024-10-07 criteria provided, single submitter research The homozygous p.Pro340His variant in NPHS1 was identified by our study in 1 individual with congenital nephrotic syndrome (PMID: 20172850). This individual, along with one other compound heterozygous proband, was reported in the literature with congenital nephrotic syndrome (PMID: 20172850). This variant has been identified in 0.007% (6/91070) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386833861). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID: 56417) and has been interpreted as likely pathogenic by Baylor Genetics and PreventionGenetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3_moderate, PM3, PM2_supporting.
Baylor Genetics RCV000049830 SCV005053646 likely pathogenic Finnish congenital nephrotic syndrome 2024-03-12 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049830 SCV000082239 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV003421960 SCV004118433 likely pathogenic NPHS1-related disorder 2024-07-23 no assertion criteria provided clinical testing The NPHS1 c.1019C>A variant is predicted to result in the amino acid substitution p.Pro340His. This variant has been reported in the homozygous or compound heterozygous state in two unrelated patients with steroid-resistant nephrotic syndrome (SRNS) (Schoeb et al. 2010. PubMed ID: 20172850). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.

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