Submissions for variant NM_178170.3(NEK8):c.133C>T (p.Arg45Trp)

dbSNP: rs1567759130

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728244	SCV000855790	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816449	SCV000956959	uncertain significance	Nephronophthisis 9	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 45 of the NEK8 protein (p.Arg45Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NEK8-related conditions. 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.
GeneDx	RCV000728244	SCV001814478	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Identified as an apparently de novo variant in a proband in published literature with multicystic kidney dysplasia in infancy (Mehawej et al., 2022) and as a de novo variant with confirmed parentage in several patients referred for genetic testing at GeneDx, but more evidence is needed to explore a potential link between heterozygous variants in the NEK8 gene and human disease; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Claus2021[Abstract], 36215968)
CeGaT Center for Human Genetics Tuebingen	RCV000728244	SCV004009765	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	NEK8: PS2:Very Strong, PM2, PP1, PS3:Supporting, PS4:Supporting
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000816449	SCV005038955	likely pathogenic	Nephronophthisis 9	2024-03-02	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 2 of the NEK8 gene that results in the amino acid substitution of Tryptophan for Arginine at codon 45 was detected. The observed variant c.133C>T (p.Arg45Trp) has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. This variant has beeen previously reported in numerous families with polycystic kidney disease and was found to be de novo in some of them (Claus et al, 2023; Mehawej et al, 2023). These papers have indicated an emerging autosomal dominant mechanism of the disease. In summary, the variant meets our criteria to be classified as likely pathogenic.