Submissions for variant NM_199242.3(UNC13D):c.2542A>C (p.Ile848Leu)

gnomAD frequency: 0.00106  dbSNP: rs144968313

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081750	SCV000638952	likely benign	Familial hemophagocytic lymphohistiocytosis 3	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762002	SCV000892237	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	UNC13D: BP4
Mendelics	RCV000762002	SCV001135107	likely benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081750	SCV001281831	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV001821540	SCV002070065	uncertain significance	not specified	2021-08-11	criteria provided, single submitter	clinical testing	The sequence change, c.2542A>C, in exon 26 results in an amino acid change, p.Ile848Leu. This sequence change has been previously described in one individual with autoimmune lymphoproliferative syndrome (PMID: 23840885), one individual with extreme hyperferritinemia (PMID: 29977033), and one individual with juvenile idiopathic arthritis (PMID: 33408077). This sequence change has been described in the gnomAD database with a low frequency of 0.28% in Ashkenazi Jewish subpopulation (dbSNP rs144968313). The p.Ile848Leu change affects a poorly conserved amino acid residue located in a domain of the UNC13D protein that is known to be functional. The p.Ile848Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Ile848Leu is a loss-of-function variant (PMID: 23840885). Due to the lack of sufficient evidence, the clinical significance of the p.Ile848Leu change remains unknown at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263768	SCV002543162	uncertain significance	Autoinflammatory syndrome	2017-10-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001081750	SCV003828023	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2020-02-28	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762002	SCV001741965	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000762002	SCV001926528	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762002	SCV001972373	likely benign	not provided		no assertion criteria provided	clinical testing