Submissions for variant NM_015102.5(NPHP4):c.1445C>T (p.Pro482Leu)

gnomAD frequency: 0.00014  dbSNP: rs372565083

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000343427	SCV000337833	uncertain significance	not provided	2015-11-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001093815	SCV000358525	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.
Illumina Laboratory Services, Illumina	RCV000332355	SCV000358526	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.
Invitae	RCV000277373	SCV001206250	uncertain significance	Nephronophthisis	2023-12-25	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 482 of the NPHP4 protein (p.Pro482Leu). This variant is present in population databases (rs372565083, gnomAD 0.02%). 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: 284999). 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 not expected to disrupt NPHP4 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002487222	SCV002787172	uncertain significance	Nephronophthisis 4; Senior-Loken syndrome 4	2022-04-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519168	SCV003599699	likely benign	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV003151009	SCV003839782	uncertain significance	not specified	2022-08-08	no assertion criteria provided	clinical testing	DNA sequence analysis of the NPHP4 gene demonstrated a sequence change, c.1445C>T, in exon 12 that results in an amino acid change, p.Pro482Leu. This sequence change has been described in the gnomAD database with a frequency of 0.022% in the non-Finnish European subpopulation (dbSNP rs372565083). The p.Pro482Leu change affects a poorly conserved amino acid residue located in a domain of the NPHP4 protein that is not known to be functional. The p.Pro482Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with NPHP4-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro482Leu change remains unknown at this time.