Submissions for variant NM_004646.4(NPHS1):c.1096A>C (p.Ser366Arg)

dbSNP: rs386833864

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001065065	SCV001230004	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the NPHS1 protein (p.Ser366Arg). This variant is present in population databases (rs386833864, gnomAD 0.0009%). This missense change has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 18709391, 20172850, 24371179, 24397250). ClinVar contains an entry for this variant (Variation ID: 56420). 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 95%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550, 18614772, 24303155). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000049833	SCV001367536	pathogenic	Finnish congenital nephrotic syndrome	2020-03-26	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3,PP4.
Fulgent Genetics, Fulgent Genetics	RCV000049833	SCV002810270	pathogenic	Finnish congenital nephrotic syndrome	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049833	SCV003922945	pathogenic	Finnish congenital nephrotic syndrome	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.1096A>C (p.Ser366Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096A>C has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g., Lenkkeri_1999, Machuca_2010). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant disrupts protein localization and folding leading to retention and eventual degradation in the endoplasmic reticulum (e.g., Liu_2001, Drozova_2013, Yoshida_2021). Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000049833	SCV004191399	pathogenic	Finnish congenital nephrotic syndrome	2024-03-28	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049833	SCV000082242	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049833	SCV002087091	pathogenic	Finnish congenital nephrotic syndrome	2021-05-21	no assertion criteria provided	clinical testing