Submissions for variant NM_199242.3(UNC13D):c.2695C>T (p.Arg899Ter)

gnomAD frequency: 0.00001  dbSNP: rs766657895

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000323586	SCV000406645	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2017-04-28	criteria provided, single submitter	clinical testing	The UNC13D c.2695C>T (p.Arg899Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg899Ter variant has been reported in two studies in which it is found in four individuals with familial hemophagocytic lymphohistiocytosis including three in a homozygous state and one in a compound heterozygous state (Elstak et al. 2012; Nijman et al. 2014). The variant was absent from 100 control individuals and is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium in a single allele only in a region of good sequence coverage so the variant is presumed to be rare. Functional studies demonstrated that the p.Arg899Ter variant results in a truncated protein which lacks the C-terminal C2 domain. This truncated protein is misfolded, showing reduced stability and increased turnover compared to wild type. Complementation assays showed a failure of the truncated protein to rescue degranulation (Elstak et al. 2012). Based on the evidence, the p.Arg899Ter variant is classified as pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000323586	SCV000943014	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg899*) in the UNC13D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs766657895, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 21755595). ClinVar contains an entry for this variant (Variation ID: 325247). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263024	SCV002543170	pathogenic	Autoinflammatory syndrome	2017-01-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702002	SCV001930639	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702002	SCV001953551	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702002	SCV001970885	pathogenic	not provided		no assertion criteria provided	clinical testing