ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.2965G>A (p.Glu989Lys) (rs116606479)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723970 SCV000227833 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000723970 SCV000581752 uncertain significance not provided 2018-09-15 criteria provided, single submitter clinical testing The E989K variant in the NPHP4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E989K variant is observed in 50/24014 (0.21%) alleles from individuals of African background, in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The E989K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E989K as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000367814 SCV000358444 uncertain significance Renal dysplasia and retinal aplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000261619 SCV000358445 uncertain significance Nephronophthisis 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000261619 SCV000636142 uncertain significance Nephronophthisis 2017-06-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 989 of the NPHP4 protein (p.Glu989Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs116606479, ExAC 0.2%). This variant has not been reported in the literature in individuals with an NPHP4-related disease. ClinVar contains an entry for this variant (Variation ID: 195608). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NPHP4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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