Submissions for variant NM_004646.4(NPHS1):c.1048T>C (p.Ser350Pro)

gnomAD frequency: 0.00001  dbSNP: rs386833863

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049832	SCV000220812	likely pathogenic	Finnish congenital nephrotic syndrome	2014-10-16	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000049832	SCV000894188	likely pathogenic	Finnish congenital nephrotic syndrome	2024-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063172	SCV001228007	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 350 of the NPHS1 protein (p.Ser350Pro). This variant is present in population databases (rs386833863, gnomAD 0.003%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 20172850, 20507940, 27594755). ClinVar contains an entry for this variant (Variation ID: 56419). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550, 15213260). This variant disrupts the p.Ser350 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been observed in individuals with NPHS1-related conditions (PMID: 27325253), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000049832	SCV001367620	likely pathogenic	Finnish congenital nephrotic syndrome	2020-02-18	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS4_MOD,PP3,PP4.
Revvity Omics, Revvity	RCV000049832	SCV003824166	pathogenic	Finnish congenital nephrotic syndrome	2022-03-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049832	SCV004191411	pathogenic	Finnish congenital nephrotic syndrome	2024-03-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000049832	SCV005086780	pathogenic	Finnish congenital nephrotic syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome type 1 (MIM#256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 and v3: 4 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 highest allele count: 10 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated CD80-like C2-set immunoglobulin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Two alternative amnio acid changes at the same position, p.(Ser350Tyr) and p.(Ser350Phe), have been reported as likely pathogenic in ClinVar. However, these variants were not deemed comparable as they have a higher Grantham score. 0801 - This variant has strong previous evidence of pathogenicity in >10 unrelated individuals (ClinVar, PMID: 29127259, PMID: 27594755, PMID: 9915943, PMID: 20172850 and PMID: 20507940). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have shown that this missense change affects protein localisation (PMID: 11726550). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049832	SCV000082241	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000049832	SCV000924463	likely pathogenic	Finnish congenital nephrotic syndrome	2018-06-15	no assertion criteria provided	research	The heterozygous p.Ser350Pro variant was identified by our study in the compound heterozygous state, along with a VUS, in one individual with nephrotic syndrome. This variant is likely pathogenic based on multiple reports in ClinVar and the literature.
Natera, Inc.	RCV000049832	SCV002087094	pathogenic	Finnish congenital nephrotic syndrome	2021-01-01	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849301	SCV002106824	likely pathogenic	Nephrotic syndrome	2017-11-10	no assertion criteria provided	literature only