Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000712426 | SCV005439249 | pathogenic | not provided | 2024-06-19 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that this variant impairs transport of mutated proteins to the cell surface (PMID: 11726550); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24742477, 21415313, 32462257, 19812541, 20507940, 9915943, 11317351, 23349334, 11726550, 29474669, 33980730) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000049886 | SCV005381053 | pathogenic | Finnish congenital nephrotic syndrome | 2024-08-15 | criteria provided, single submitter | clinical testing | Variant summary: NPHS1 c.2417C>A (p.Ala806Asp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251454 control chromosomes. c.2417C>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (example: Lenkkeri_1999, Santin_2009, Lovric_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect impairs cellular localization (Liu_2001). The following publications have been ascertained in the context of this evaluation (PMID: 9915943, 19812541, 11726550, 24742477). ClinVar contains an entry for this variant (Variation ID: 56473). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000049886 | SCV004191424 | pathogenic | Finnish congenital nephrotic syndrome | 2024-02-15 | criteria provided, single submitter | clinical testing | |
| Vasylyeva lab, |
RCV000049886 | SCV004123130 | pathogenic | Finnish congenital nephrotic syndrome | 2020-09-16 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000712426 | SCV001385277 | pathogenic | not provided | 2024-03-13 | 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. |
| Illumina Laboratory Services, |
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. |
| 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. |
| Equipe Genetique des Anomalies du Developpement, |
RCV000049886 | SCV000803816 | pathogenic | Finnish congenital nephrotic syndrome | 2016-06-07 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000049886 | SCV000220399 | likely pathogenic | Finnish congenital nephrotic syndrome | 2014-06-12 | criteria provided, single submitter | literature only | |
| Solve- |
RCV000049886 | SCV005091303 | likely pathogenic | Finnish congenital nephrotic syndrome | 2022-06-01 | no assertion criteria provided | provider interpretation | Variant confirmed as disease-causing by referring clinical team |
| Natera, |
RCV000049886 | SCV001460528 | pathogenic | Finnish congenital nephrotic syndrome | 2020-09-16 | no assertion criteria provided | clinical testing | |
| Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000049886 | SCV000082295 | likely pathogenic | Finnish congenital nephrotic syndrome | no assertion criteria provided | not provided | Converted during submission from probable-pathogenic to Likely pathogenic. |