Submissions for variant NM_199242.3(UNC13D):c.2983G>C (p.Ala995Pro)

gnomAD frequency: 0.00105  dbSNP: rs138760432

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081751	SCV000638957	benign	Familial hemophagocytic lymphohistiocytosis 3	2025-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762001	SCV000892236	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	UNC13D: BP4
Mendelics	RCV000762001	SCV001135104	likely benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081751	SCV001285894	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.
GeneDx	RCV000762001	SCV001769981	uncertain significance	not provided	2020-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has been previously reported in cis with I848L in unrelated patients who had features of macrophage activation syndrome and autoimmune lymphoproliferative syndrome (Zhang et al., 2008; Arico et al., 2013; Kernan et al., 2018).; Transfection study of the I848L and A995P variants showed that these variants, both alone and in combination, decreased granule exocytosis when compared to wild type (Arico et al., 2013); This variant is associated with the following publications: (PMID: 33408077, 29977033, 18759271, 23840885, 29864493)
Genetic Services Laboratory, University of Chicago	RCV001821541	SCV002070063	uncertain significance	not specified	2021-08-11	criteria provided, single submitter	clinical testing	The sequence change, c.2983G>C, in exon 31 results in an amino acid change, p.Ala995Pro. 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 0.27% in Ashkenazi Jewish subpopulation (dbSNP rs138760432). The p.Ala995Pro change affects a poorly conserved amino acid residue located in a domain of the UNC13D protein that is known to be functional. The p.Ala995Pro substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Ala995Pro is a loss-of-function variant (PMID: 23840885). Due to the lack of sufficient evidence, the clinical significance of the p.Ala995Pro change remains unknown at this time.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263769	SCV002543177	uncertain significance	Autoinflammatory syndrome	2017-10-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001081751	SCV003828028	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2020-02-28	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762001	SCV001744520	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000762001	SCV001928903	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762001	SCV001969571	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745456	SCV005363358	uncertain significance	UNC13D-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The UNC13D c.2983G>C variant is predicted to result in the amino acid substitution p.Ala995Pro. This variant was reported in an individual with autoimmune lymphoproliferative syndrome who had inherited it as part of a haplotype that also contained another variant p.Ile848Leu from the unaffected mother (Aricò et al. 2013. PubMed ID: 23840885). Both variants have also been reported in an individual with septic shock and macrophage activation syndrome (Kernan et al. 2018. PubMed ID: 29977033) as well as in two individuals with polyarticular juvenile idiopathic arthritis (Meng et al. 2021. PubMed ID: 33408077). In vitro studies in a mastocytoma cell line showed that both variants, when expressed together as well as separately, resulted in defective secretory granule exocytosis; however, it is unclear how this finding relates to cells of the immune system in vivo (Aricò et al. 2013. PubMed ID: 23840885). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.