ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.1715G>A (p.Ser572Asn) (rs386833889)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487117 SCV000568764 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The S572N variant in the NPHS1 gene has been reported previously in the presence of a second NPHS1 variant in a few individuals with nephrotic syndrome (Gigante et al., 2005; Schoeb et al., 2010). The S572N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The S572N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S572N as a pathogenic variant.
Counsyl RCV000049860 SCV000789515 likely pathogenic Finnish congenital nephrotic syndrome 2017-02-09 criteria provided, single submitter clinical testing
Invitae RCV000487117 SCV001233250 pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 572 of the NPHS1 protein (p.Ser572Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs386833889, ExAC 0.002%). This variant has been observed in individual(s) with congenital nephrotic syndrome (PMID: 15906409, 20172850, 29474669). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56447). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ser572 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been observed in individuals with NPHS1-related conditions (PMID: 18503012, 26248470), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049860 SCV000082269 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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