Submissions for variant NM_178170.3(NEK8):c.1795C>T (p.Arg599Ter)

gnomAD frequency: 0.00007  dbSNP: rs375661404

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001699113	SCV002038937	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Loss of NEK8 expression was reported in fibroblasts from affected fetuses with this homozygous variant (Frank et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26697755, 30924587, 31980526, 31589614, 23418306, 26862157)
Fulgent Genetics, Fulgent Genetics	RCV002483083	SCV002784663	pathogenic	Nephronophthisis 9; Renal-hepatic-pancreatic dysplasia 2	2022-04-06	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000055629	SCV003920972	likely pathogenic	Renal-hepatic-pancreatic dysplasia 2	2023-03-23	criteria provided, single submitter	clinical testing	This variant was observed in heterozygosity with variant c.618G>A
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000055629	SCV004808066	likely pathogenic	Renal-hepatic-pancreatic dysplasia 2	2024-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055629	SCV005185988	pathogenic	Renal-hepatic-pancreatic dysplasia 2	2024-05-02	criteria provided, single submitter	clinical testing	Variant summary: NEK8 c.1795C>T (p.Arg599X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.8e-05 in 251416 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEK8 causing Renal-Hepatic Dysplasia 2. c.1795C>T has been reported in the literature in multiple homozygous individuals affected with Renal-Hepatic Dysplasia 2 (e.g., Frank_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function; studies on patient fibroblasts demonstrated a loss of NEK8 expression. The following publication has been ascertained in the context of this evaluation (PMID: 23418306). ClinVar contains an entry for this variant (Variation ID: 65408). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000055629	SCV000083854	pathogenic	Renal-hepatic-pancreatic dysplasia 2	2013-06-01	no assertion criteria provided	literature only
Reproductive Development, Murdoch Childrens Research Institute	RCV000766162	SCV000882496	uncertain significance	Premature ovarian insufficiency	2018-01-10	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699113	SCV001926445	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699113	SCV001955861	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699113	SCV001969330	pathogenic	not provided		no assertion criteria provided	clinical testing