ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.133C>T (p.Gln45Ter)

gnomAD frequency: 0.00004  dbSNP: rs370210428
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681812 SCV000890172 pathogenic not provided 2023-09-08 criteria provided, single submitter clinical testing Reported as a heterozygous variant in unrelated patients with nephropathy or end stage renal disease in published literature; however, a second variant in NPHP4 was not reported (Halbritter et al., 2013; Groopman et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31964843, 23559409, 34216551, 30586318)
Invitae RCV001237139 SCV001409890 pathogenic Nephronophthisis 2023-06-14 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 562355). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with a nephronophthisis-related ciliopathy (PMID: 23559409). This variant is present in population databases (rs370210428, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Gln45*) 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).
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center RCV003453402 SCV004190153 likely pathogenic Senior-Loken syndrome 4 2020-11-05 criteria provided, single submitter clinical testing The c.133C>T variant in the NPHP4 gene is a heterozygous nonsense variant, which results in a premature stop codon at the position 45 (p.Gln45Ter). This premature truncation occurs in coding exon 2 of the NPHP4 gene (30 exons total; NM_015102.5). Loss-of-function variants in NPHP4 have been established to be pathogenic (PMIDs: 12205563, 23559409). Several different loss-of-function variants distal to this one have been described to be disease causing. This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00003210, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in an individual with nephronophthisis-related ciliopathy (PMID: 23559409).
Gharavi Laboratory, Columbia University RCV000681812 SCV000809283 pathogenic not provided 2018-09-16 no assertion criteria provided research

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