ClinVar Miner

Submissions for variant NM_004646.4(NPHS1):c.2417C>A (p.Ala806Asp)

gnomAD frequency: 0.00002  dbSNP: rs386833912
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049886 SCV000220399 likely pathogenic Finnish congenital nephrotic syndrome 2014-06-12 criteria provided, single submitter literature only
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000049886 SCV000803816 pathogenic Finnish congenital nephrotic syndrome 2016-06-07 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000712426 SCV000842919 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Illumina Laboratory Services, Illumina RCV000049886 SCV000915827 pathogenic Finnish congenital nephrotic syndrome 2018-08-22 criteria provided, single submitter clinical testing The NPHS1 c.2417C>A (p.Ala806Asp) variant has been reported in at least five studies and is found in a homozygous state in three probands and in a compound heterozygous state in two probands with congenital Finnish nephrosis (Lenkerri et al. 1999; Santin et al. 2009; Santin et al. 2011; Lovric et al. 2014; Machuca et al. 2014; Berody et al. 2018). The p.Ala806Asp variant was absent from 30 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele so the variant is presumed to be rare. Immunostaining of cells with wildtype NPHS1 demonstrated expression at the plasma membrane, whereas in cells containing the p.Ala806Asp variant there was no detectable surface staining observed (Liu et al. 2001). Based on the evidence, the p.Ala806Asp 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.
Invitae RCV000712426 SCV001385277 pathogenic not provided 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 806 of the NPHS1 protein (p.Ala806Asp). This variant is present in population databases (rs386833912, gnomAD 0.002%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 20507940, 21415313, 24742477, 33980730). ClinVar contains an entry for this variant (Variation ID: 56473). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550). This variant disrupts the p.Ala806 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23349334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Vasylyeva lab, Texas Tech University Health Sciences Center RCV000049886 SCV004123130 pathogenic Finnish congenital nephrotic syndrome 2020-09-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000049886 SCV004191424 pathogenic Finnish congenital nephrotic syndrome 2023-08-25 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049886 SCV000082295 probable-pathogenic Finnish congenital nephrotic syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Natera, Inc. RCV000049886 SCV001460528 pathogenic Finnish congenital nephrotic syndrome 2020-09-16 no assertion criteria provided clinical testing

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