Submissions for variant NM_004646.4(NPHS1):c.1868G>T (p.Cys623Phe)

gnomAD frequency: 0.00007  dbSNP: rs386833895

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049866	SCV000220231	likely pathogenic	Finnish congenital nephrotic syndrome	2014-04-08	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000049866	SCV000411567	pathogenic	Finnish congenital nephrotic syndrome	2017-04-27	criteria provided, single submitter	clinical testing	The NPHS1 c.1868G>T (p.Cys623Phe) variant has been reported in six studies and is found in a total of eight patients with congenital Finnish nephrosis, including in one patient in a homozygous state, six patients (including a sibling pair) in a compound heterozygous state, and one patient in a heterozygous state in whom a second variant was not detected (Lenkkeri et al. 1999; Koziell et al. 2002; Schultheiss et al. 2004; Santin et al. 2009; Buscher et al. 2010; Schoeb et al. 2010). The p.Cys623Phe variant was absent from 173 controls but is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated impaired intracellular trafficking of the p.Cys623Phe variant protein with retention in the endoplasmic reticulum compared to localization of the wild type protein at the plasma membrane (Liu et al. 2001). Based on the collective evidence, the p.Cys623Phe 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.
Fulgent Genetics, Fulgent Genetics	RCV000049866	SCV000893523	likely pathogenic	Finnish congenital nephrotic syndrome	2021-07-13	criteria provided, single submitter	clinical testing
Invitae	RCV000811777	SCV000952063	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 623 of the NPHS1 protein (p.Cys623Phe). This variant is present in population databases (rs386833895, gnomAD 0.008%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 11854170, 15338398, 18709391, 19812541, 20172850, 24902943). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56453). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000811777	SCV001825075	likely pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrated that C623F significantly impaired tyrosine phosphorylation and cell surface translocation of mutant protein (Cooper et al., 2018; Liu et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18709391, 27019444, 11317351, 30212551, 20172850, 21415313, 11726550, 9915943, 30655312, 15503167, 28921387, 24902943, 20798252, 11854170, 15338398, 31589614, 19812541)
Vasylyeva lab, Texas Tech University Health Sciences Center	RCV000049866	SCV004123128	pathogenic	Finnish congenital nephrotic syndrome	2019-01-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049866	SCV004191383	pathogenic	Finnish congenital nephrotic syndrome	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049866	SCV004240961	pathogenic	Finnish congenital nephrotic syndrome	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: NPHS1 c.1868G>T (p.Cys623Phe) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250770 control chromosomes (gnomAD). c.1868G>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome (examples: Hinkes_2007, Schoeb_2010, Cooper_2018, Tan_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant disrupts the cell surface translocation of mutant protein (Cooper_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30212551, 17371932, 20172850, 28921387). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049866	SCV000082275	probable-pathogenic	Finnish congenital nephrotic syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049866	SCV001460537	pathogenic	Finnish congenital nephrotic syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000811777	SCV001931748	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000811777	SCV001956158	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849305	SCV002106565	pathogenic	Nephrotic syndrome	2019-01-17	no assertion criteria provided	literature only