ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.1462C>T (p.Arg488Ter)

gnomAD frequency: 0.00009  dbSNP: rs778043242
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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 RCV000353231 SCV000358524 uncertain significance NPHP4-related disorder 2017-04-27 criteria provided, single submitter clinical testing The NPHP4 c.1462C>T (p.Arg488Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg488Ter variant has been reported in a single study in which it was found in a homozygous state in one individual with nephronophthisis (Hoefele et al. 2005). The p.Arg488Ter variant was absent from at least 86 controls and is reported at a frequency of 0.00020 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the potential impact of stop-gained variants and the limited evidence from the literature, the p.Arg488Ter variant is classified a variant of unknown significance but suspicious for pathogenicity for NPHP4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Eurofins Ntd Llc (ga) RCV000728192 SCV000855736 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001388046 SCV001588864 pathogenic Nephronophthisis 2023-02-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg488*) in the NPHP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHP4 are known to be pathogenic (PMID: 12205563, 23559409). This variant is present in population databases (rs778043242, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with nephronophthisis (PMID: 15776426). ClinVar contains an entry for this variant (Variation ID: 297820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Precision Medicine Center, Zhengzhou University RCV004577521 SCV004218447 pathogenic Nephronophthisis 4 2023-12-01 criteria provided, single submitter clinical testing PVS1,PM2_p,PM3

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