Submissions for variant NM_199242.3(UNC13D):c.1389+1G>A

gnomAD frequency: 0.00006  dbSNP: rs777759523

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000380656	SCV000329946	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19704116, 25573973, 25525159, 24916509, 30487145, 32542393, 14622600)
Illumina Laboratory Services, Illumina	RCV000002076	SCV000406672	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2017-04-27	criteria provided, single submitter	clinical testing	The UNC13D c.1389+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in six studies in which it is found in a total of ten individuals with familial hemophagocytic lymphohistiocytosis, including two siblings in a homozygous state, seven individuals in a compound heterozygous state, and one in a heterozygous state in whom a second variant was not detected (Feldmann et al. 2003; Zur Stadt et al. 2006; Santoro et al. 2008; Wood et al. 2009; Sieni et al. 2011; Nakamura et al. 2015). The variant was absent from ten controls but is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of splice donor variants and the supporting evidence from the literature, the c.1389+1G>A 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	RCV000002076	SCV000829598	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the UNC13D gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs777759523, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 14622600, 18492689, 19704116, 21248318, 25573973). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1999). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000380656	SCV000861288	pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000002076	SCV000894151	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2018-10-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262537	SCV002543131	pathogenic	Autoinflammatory syndrome	2020-11-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002076	SCV004244352	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2024-01-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
OMIM	RCV000002076	SCV000022234	pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2003-11-14	no assertion criteria provided	literature only