ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.3574C>T (p.Arg1192Trp) (rs139022622)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000271940 SCV000343499 likely benign not specified 2016-06-30 criteria provided, single submitter clinical testing
Invitae RCV000168448 SCV000219145 uncertain significance Nephronophthisis 2014-10-07 no assertion criteria provided clinical testing This sequence change replaces arginine with tryptophan at codon 1192 of the NPHP4 protein (p.Arg1192Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This sequence change has been reported in the literature and is present in population databases (rs139022622, 0.2%). It was found to be heterozygous in two patients affected with nephronophthisis (PMID: 15776426) and in a single patient affected with cardiovascular malformations, midline liver, asplenia, intestinal malrotation and mild hepatomegaly (PMID: 22550138). Knockdown of NPHP4 in zebra fish results in shorter cilia and reduced fluid flow at the embryonal node (PMID: 22550138). Although these results suggest that pathogenic sequence changes in NPHP4 may potentially cause heterotaxy, the functional and clinical significance of this c.3574C>T missense change is uncertain at this time. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "deleterious"; MutationTaster: "polymorphism"; Align-GVGD: "Class C0").

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