Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000007278 | SCV000800602 | uncertain significance | Finnish congenital nephrotic syndrome | 2017-09-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001851717 | SCV002175671 | pathogenic | not provided | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 822 of the NPHS1 protein (p.Val822Met). This variant is present in population databases (rs267606918, gnomAD 0.02%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 17290294, 31937884). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6875). 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 not expected to disrupt NPHS1 protein function. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 17290294). For these reasons, this variant has been classified as Pathogenic. |
| 3billion | RCV000007278 | SCV002572960 | uncertain significance | Finnish congenital nephrotic syndrome | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NPHS1-related disorder (ClinVar ID: VCV000006875 / PMID: 17290294). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000007278 | SCV003929377 | pathogenic | Finnish congenital nephrotic syndrome | 2023-04-25 | criteria provided, single submitter | clinical testing | Variant summary: NPHS1 c.2464G>A (p.Val822Met) results in a conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251512 control chromosomes (gnomAD and publication data). c.2464G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Nephrotic Syndrome (Kitamura_2007, Nagano_2020, Park_2020). These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and this variant results in reduced cell surface targeting and ineffective assembly of signaling microdomains (Kitamura_2007, Shono_2009). The following publications have been ascertained in the context of this evaluation (PMID: 17290294, 31937884, 32604935, 19443487). Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000007278 | SCV004191413 | pathogenic | Finnish congenital nephrotic syndrome | 2024-03-12 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000007278 | SCV000027474 | pathogenic | Finnish congenital nephrotic syndrome | 2007-05-01 | no assertion criteria provided | literature only |