ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.257C>T (p.Pro86Leu)

gnomAD frequency: 0.00027  dbSNP: rs201998215
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000296483 SCV000358557 uncertain significance Senior-Loken syndrome 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000349088 SCV000358558 uncertain significance Nephronophthisis 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga) RCV000592094 SCV000708791 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764008 SCV000894960 uncertain significance Nephronophthisis 4; Senior-Loken syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075645 SCV001241272 uncertain significance Retinal dystrophy 2019-02-23 criteria provided, single submitter clinical testing
Invitae RCV001347432 SCV001541691 uncertain significance Nephronophthisis 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the NPHP4 protein (p.Pro86Leu). This variant is present in population databases (rs201998215, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NPHP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 297830). 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. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002294255 SCV002587476 uncertain significance Kidney disorder 2016-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000592094 SCV002819024 uncertain significance not provided 2022-07-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV003298360 SCV004004809 uncertain significance Inborn genetic diseases 2023-03-28 criteria provided, single submitter clinical testing The c.257C>T (p.P86L) alteration is located in exon 3 (coding exon 2) of the NPHP4 gene. This alteration results from a C to T substitution at nucleotide position 257, causing the proline (P) at amino acid position 86 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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