Submissions for variant NM_199242.3(UNC13D):c.2180G>A (p.Arg727Gln)

gnomAD frequency: 0.00013  dbSNP: rs747390615

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000355372	SCV000406657	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2017-04-28	criteria provided, single submitter	clinical testing	The UNC13D c.2180G>A (p.Arg727Gln) variant has been reported in one study in which it is found in a compound heterozygous state in one individual with familial hemophagocytic lymphohistiocytosis (Sieni et al. 2011). The p.Arg727Gln variant was absent from 100 controls but is reported at a frequency of 0.00137 in the South Asian population of the Exome Aggregation Consortium. Significantly lower granule release was demonstrated in individual cells in a degranulation assay based on quantifying CD107a expression on the cell surface (Sieni et al. 2011). The evidence for this variant is limited. The p.Arg727Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000355372	SCV001110684	likely benign	Familial hemophagocytic lymphohistiocytosis 3	2024-01-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263026	SCV002543149	uncertain significance	Autoinflammatory syndrome	2019-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401341	SCV004122551	uncertain significance	not specified	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.2180G>A (p.Arg727Gln) results in a conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 173178 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00044 vs 0.0027), allowing no conclusion about variant significance. c.2180G>A has been reported in the literature in either the compound heterozygous or heterozygous state in individuals affected with Familial Hemophagocytic Lymphohistiocytosis or other immune dysregulation disorders, without strong evidence for causality (e.g. Sieni_2011, Batlle-Maso_2020, Xinh_2021, Allain_2023) . These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. At least one publication reports experimental evidence evaluating an impact on protein function (Shibata_2018). These results suggested the variant may have mild to moderately reduced stability, but showed no damaging effect on degranulation and cytolytic activity in vitro and was capable of restoring the degranulation and cytolytic activity of a familial hemophagocytic lymphohistiocytosis cell line to levels comparable with cells transfected with the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 36155879, 32222431, 29549174, 21248318, 34339548). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either uncertain significance or likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.