ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.2260G>A (p.Gly754Arg)

gnomAD frequency: 0.00003  dbSNP: rs373962831
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000283252 SCV000358474 uncertain significance Nephronophthisis 4 2017-04-28 criteria provided, single submitter clinical testing The NPHP4 c.2260G>A (p.Gly754Arg) missense variant has been reported in one study in which it is found in a compound heterozygous state with a splice site variant in two siblings with nephronophthisis (Otto et al. 2002). These siblings inherited the p.Gly754Arg variant from their unaffected father and the splice site variant from their mother. The variant was absent from 92 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, although this is based on only one allele. The evidence for this variant is limited. The p.Gly754Arg variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for nephronophthisis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV000338114 SCV000358475 uncertain significance Senior-Loken syndrome 4 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Eurofins Ntd Llc (ga) RCV000592408 SCV000709023 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing
Invitae RCV001379795 SCV001577666 pathogenic Nephronophthisis 2023-05-12 criteria provided, single submitter clinical testing 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 NPHP4 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPHP4 function (PMID: 16339905, 17558407). ClinVar contains an entry for this variant (Variation ID: 297808). This missense change has been observed in individual(s) with chronic kidney disease and/or nephronophthisis (PMID: 12205563, 27491411, 34295353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs373962831, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 754 of the NPHP4 protein (p.Gly754Arg).

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