ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.3364A>C (p.Thr1122Pro) (rs375836844)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595557 SCV000707775 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778988 SCV000915426 uncertain significance NPHP4-Related Disorders 2018-11-19 criteria provided, single submitter clinical testing The NPHP4 c.3364A>C (p.Thr1122Pro) variant is a missense variant that has been reported in a compound heterozygous state with a frameshift variant in one individual with nephronophthisis (Otto et al. 2011). This variant was absent from 96 healthy control individuals but is reported at a frequency of 0.000213 in the European (non-Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. Based on the limited evidence, the p.Thr1122Pro variant is classified as a variant of uncertain 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.
Invitae RCV001055295 SCV001219682 uncertain significance Nephronophthisis 2019-12-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 1122 of the NPHP4 protein (p.Thr1122Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs375836844, ExAC 0.01%). This variant has been observed in individual(s) with nephronophthisis (PMID: 21068128). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 501425). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Blueprint Genetics RCV001074439 SCV001240023 uncertain significance Retinal dystrophy 2017-02-20 criteria provided, single submitter clinical testing

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