ClinVar Miner

Submissions for variant NM_199242.3(UNC13D):c.247C>T (p.Arg83Ter)

dbSNP: rs1274685768
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778518 SCV000914797 likely pathogenic Familial hemophagocytic lymphohistiocytosis 3 2017-04-28 criteria provided, single submitter clinical testing The UNC13D c.247C>T (p.Arg83Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg83Ter variant has been reported in two studies and found in a total of two individuals affected with familial hemophagocytic lymphohistiocytosis, including one each in a homozygous and compound heterozygous state (Rudd et al. 2008; Seo et al. 2013). The variant was absent from 214 control individuals and is reported at a frequency of 0.000055 in the East Asian population of the Genome Aggregation Database but this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. The truncation is predicted to result in complete loss of the region responsible for binding to Rab27a and association with secretory granules. Based on the potential impact of stop-gained variants and the evidence, the p.Arg83Ter variant is classified as likely pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002263969 SCV002543159 likely pathogenic Autoinflammatory syndrome 2016-12-12 criteria provided, single submitter clinical testing
Invitae RCV000778518 SCV004297567 pathogenic Familial hemophagocytic lymphohistiocytosis 3 2023-04-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 631788). This premature translational stop signal has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 17993578, 34677667). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg83*) 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).

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