Submissions for variant NM_199242.3(UNC13D):c.2341G>A (p.Val781Ile)

gnomAD frequency: 0.00162  dbSNP: rs149871493

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001083279	SCV000406652	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000734023	SCV000581953	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in an individual with autoimmune lymphoproliferative syndrome, however, segregation information was not included, and the patient was only tested for variants in two genes (Arico et al., 2013); Functional studies in transfected cell lines displayed a loss-of-function effect, reducing granule exocytosis (Arico et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 29864493, Buttini_2013_PhDThesis, 34868048, 23840885)
Invitae	RCV001083279	SCV000761706	likely benign	Familial hemophagocytic lymphohistiocytosis 3	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000734023	SCV000862134	uncertain significance	not provided	2018-06-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000734023	SCV000892494	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	UNC13D: BP4, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263025	SCV002543155	likely benign	Autoinflammatory syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265731	SCV002547759	likely benign	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.2341G>A (p.Val781Ile) results in a conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250864 control chromosomes, predominantly at a frequency of 0.0029 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2341G>A has been reported in the literature as a non-informative genotype in at-least one individual with Autoimmune lymphoproliferative syndrome (ALPS) (example, Arico_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Arico_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Genetics and Molecular Pathology, SA Pathology	RCV001083279	SCV002556545	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2020-08-28	criteria provided, single submitter	clinical testing	BP4
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000734023	SCV001740625	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000734023	SCV001932363	likely benign	not provided		no assertion criteria provided	clinical testing