Submissions for variant NM_199242.3(UNC13D):c.753+3G>A

gnomAD frequency: 0.00627  dbSNP: rs116229331

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422858	SCV000521278	likely benign	not specified	2016-06-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086175	SCV000638961	benign	Familial hemophagocytic lymphohistiocytosis 3	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000544050	SCV001135111	benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086175	SCV001286569	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	RCV000422858	SCV002069179	benign	not specified	2021-10-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261085	SCV002542657	likely benign	Autoinflammatory syndrome	2018-05-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000422858	SCV004029966	benign	not specified	2023-07-18	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.753+3G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 251412 control chromosomes, predominantly at a frequency of 0.018 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7 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 African or African-American origin. c.753+3G>A has been reported in the literature in individuals affected with Hemophagocytic Lymphohistiocytosis (Chang_2011) without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21370424). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000544050	SCV004144271	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	UNC13D: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003970151	SCV004777982	likely benign	UNC13D-related disorder	2020-03-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).