Submissions for variant NM_004646.4(NPHS1):c.2227C>T (p.Arg743Cys)

gnomAD frequency: 0.00006  dbSNP: rs386833909

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049882	SCV000485923	likely pathogenic	Finnish congenital nephrotic syndrome	2016-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797708	SCV000937283	pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 743 of the NPHS1 protein (p.Arg743Cys). This variant is present in population databases (rs386833909, gnomAD 0.008%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 10972661, 20172850, 20507940, 24902943, 28117080). ClinVar contains an entry for this variant (Variation ID: 56469). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on NPHS1 function (PMID: 11726550, 24142548, 24303155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000797708	SCV001771364	likely pathogenic	not provided	2024-11-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32377865, 24142548, 11726550, 24303155, 33591954, 9915943, 24902943, 35372954, 11854170, 33089377, 20172850, 28117080, 10972661, 20507940)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049882	SCV001983586	pathogenic	Finnish congenital nephrotic syndrome	2021-09-14	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.2227C>T (p.Arg743Cys) results in a non-conservative amino acid change located in the Spacer region between Ig-6 and Ig-7 domains (Liu_2001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251448 control chromosomes. c.2227C>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (example, Lenkkeri_1999, Patrakka_2000, Liu_2001, Kari_2014, Bierzynska_2017, 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. The most pronounced variant effect results in ERAD (endoplasmic reticulum associated degradation) while not impacting trafficking to the cell surface (example, Drozova_2013, Miyai_2014, Yoshida_2021). Endoplasmic reticulum associated degradation is required for nephrin maturation and kidney glomerular filtration function (Yoshida_2021). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000049882	SCV002775295	likely pathogenic	Finnish congenital nephrotic syndrome	2022-05-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049882	SCV004191374	likely pathogenic	Finnish congenital nephrotic syndrome	2024-03-14	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000049882	SCV004232717	pathogenic	Finnish congenital nephrotic syndrome	2023-12-01	criteria provided, single submitter	research
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049882	SCV000082291	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328086	SCV001449378	pathogenic	Nephrotic syndrome	2018-02-22	no assertion criteria provided	clinical testing	This individual is homozygous for the c.2227C>T p.(Arg743Cys) variant in the NPHS1 gene. This variant has been reported in the ExAC database (http://exac.broadinstitute.org) with a very low allele frequency of 0.0016% (2 out of 121,386 alleles). It has also been reported in compound heterozygote state in mulitple patients with congenital nephrotic syndrome of Finnish type (see references). In addition, in vitro studies found that the p.Arg732Cys mutant peptide did not fold correctly and was rapidly degraded in the endoplasmic reticulum (Drozdova et al. 2013 Physiol Rep 1:e00086). In silico analysis of pathogenicity (through Alamut Visual v.2.8.1) using PolyPhen2, SIFT and MutationTaster all predict that this variant is likely to be pathogenic. This variant is considered to be pathogenic according to the ACMG guidelines.
Natera, Inc.	RCV000049882	SCV001460532	likely pathogenic	Finnish congenital nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing