Submissions for variant NM_015102.5(NPHP4):c.3181G>A (p.Val1061Ile)

gnomAD frequency: 0.00052  dbSNP: rs143020939

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153584	SCV000203122	uncertain significance	not provided	2018-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765246	SCV000896493	uncertain significance	Nephronophthisis 4; Senior-Loken syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098351	SCV001254711	uncertain significance	Nephronophthisis 4	2017-09-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098352	SCV001254712	uncertain significance	Senior-Loken syndrome 4	2017-09-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001226576	SCV001398896	uncertain significance	Nephronophthisis	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1061 of the NPHP4 protein (p.Val1061Ile). This variant is present in population databases (rs143020939, gnomAD 0.1%). 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: 167372). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000153584	SCV004227722	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150953	SCV003839783	uncertain significance	not specified	2022-05-10	no assertion criteria provided	clinical testing	DNA sequence analysis of the NPHP4 gene demonstrated a sequence change, c.3181G>A, in exon 22 that results in an amino acid change, p.Val1061Ile. This sequence change has been described in the gnomAD database with a frequency of 0.10% in the African/African American subpopulation (dbSNP rs143020939). The p.Val1061Ile 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.Val1061Ile 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.Val1061Ile change remains unknown at this time.