Submissions for variant NM_199242.3(UNC13D):c.766C>T (p.Arg256Ter)

dbSNP: rs121434352

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760447	SCV000890331	pathogenic	not provided	2019-01-18	criteria provided, single submitter	clinical testing	The R256X nonsense variant has been reported previously in trans with another pathogenic variant in association with familial hemophagocytic lymphohistiocytosis (Feldmann et al., 2003). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret this variant as pathogenic.
Illumina Laboratory Services, Illumina	RCV000002077	SCV000914796	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2018-08-29	criteria provided, single submitter	clinical testing	The UNC13D c.766C>T (p.Arg256Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The c.766C>T (p.Arg256Ter) variant has been reported in five studies and is found in seven individuals with familial hemophagocytic lymphohistiocytosis in a compound heterozygous state (Feldmann et al. 2003; Zur Stadt et al. 2006; Nagai et al. 2010; Zhizhuo et al. 2012; Qian et al. 2014). The variant was absent from 276 control subjects and is present at a frequency of 0.000046 in the European (non-Finnish) population of the Exome Aggregation Consortium. Western blotting experiments showed that the p.Arg256Ter variant resulted in an absence of protein expression (Nagai et al. 2010). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Arg256Ter variant is considered to be pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000002077	SCV000938827	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg256*) 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 (rs121434352, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 14622600, 21152410, 21674762, 24470399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2000). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262538	SCV002543193	pathogenic	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000002077	SCV004806636	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000002077	SCV000022235	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2003-11-14	no assertion criteria provided	literature only