ClinVar Miner

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

gnomAD frequency: 0.00007  dbSNP: rs386833895
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Total submissions: 13
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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 2023-10-18 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

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