Submissions for variant NM_003647.3(DGKE):c.1679A>G (p.Gln560Arg)

gnomAD frequency: 0.00190  dbSNP: rs61751972

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000395700	SCV000343682	uncertain significance	not provided	2016-08-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000395700	SCV002408971	benign	not provided	2024-01-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417911	SCV004109265	uncertain significance	DGKE-related disorder	2022-12-18	criteria provided, single submitter	clinical testing	The DGKE c.1679A>G variant is predicted to result in the amino acid substitution p.Gln560Arg. This variant has been reported in a patient with hemolytic uremic syndrome and Denys-Drash syndrome that can be explained by a de novo pathogenic variant in the WT1 gene (Alge et al. 2017. PubMed ID: 28720077). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-54940127-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Molecular Genetics, Royal Melbourne Hospital	RCV003993918	SCV004812734	likely benign	Immunoglobulin-mediated membranoproliferative glomerulonephritis	2023-06-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689705	SCV005185919	likely benign	not specified	2024-05-03	criteria provided, single submitter	clinical testing	Variant summary: DGKE c.1679A>G (p.Gln560Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 221064 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 27 fold of the estimated maximal expected allele frequency for a pathogenic variant in DGKE causing Genetic Atypical Hemolytic Uremic Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1679A>G has been reported in the literature in individuals affected with genetic atypical hemolytic uremic syndrome without strong evidence of causality (e.g. Alge_2017, Connaughton_2023) . These report(s) do not provide unequivocal conclusions about association of the variant with Genetic Atypical Hemolytic Uremic Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28720077, 37466676). ClinVar contains an entry for this variant (Variation ID: 289334). Based on the evidence outlined above, the variant was classified as likely benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000395700	SCV001954732	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000395700	SCV001975396	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000395700	SCV001978248	likely benign	not provided		no assertion criteria provided	clinical testing