ClinVar Miner

Submissions for variant NM_004646.3(NPHS1):c.1868G>T (p.Cys623Phe) (rs386833895)

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Total submissions: 5
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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 Clinical Services Laboratory,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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000811777 SCV000952063 pathogenic not provided 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 623 of the NPHS1 protein (p.Cys623Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs386833895, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another NPHS1 variant in individuals affected with nephrotic syndrome (PMID: 18709391, 19812541, 20172850, 24902943, 15338398, 11854170). ClinVar contains an entry for this variant (Variation ID: 56453). Experimental studies have shown that this missense change disrupts protein function (PMID: 11726550). For these reasons, this variant has been 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.

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