ClinVar Miner

Submissions for variant NM_153240.5(NPHP3):c.3422T>C (p.Leu1141Pro)

gnomAD frequency: 0.00001  dbSNP: rs1057521090
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434888 SCV000521039 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NPHP3 gene. The L1141P variant has been reported previously in the heterozygous state in two related individuals with nephronophthisis; however, a second NPHP3 variant was not identified in either individual (Olbrich et al., 2003). The L1141P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L1141P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001318647 SCV001509359 uncertain significance Nephronophthisis 2021-08-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1141 of the NPHP3 protein (p.Leu1141Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of nephronophthisis (PMID: 12872122; Invitae). 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: 381594). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust RCV003325954 SCV003853421 likely pathogenic Fibrotic kidney disease 2023-03-23 criteria provided, single submitter clinical testing

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