Submissions for variant NM_199242.3(UNC13D):c.869C>T (p.Ser290Leu)

gnomAD frequency: 0.00001  dbSNP: rs202020396

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001234601	SCV001407255	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 290 of the UNC13D protein (p.Ser290Leu). This variant is present in population databases (rs202020396, gnomAD 0.01%). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 16278825, 24916509). ClinVar contains an entry for this variant (Variation ID: 960980). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001234601	SCV001524134	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2020-07-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844275	SCV002104130	uncertain significance	not specified	2022-02-26	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.869C>T (p.Ser290Leu) results in a non-conservative amino acid change in 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 6.9e-05 in 246780 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (6.9e-05 vs 0.0027), allowing no conclusion about variant significance. c.869C>T has been reported in the literature as a heterozygous variant in individuals with Familial Hemophagocytic Lymphohistiocytosis, and a possible digenic model of inheritance has also been proposed in one study (examples, Stadt_2006, Zhang_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264238	SCV002543196	uncertain significance	Autoinflammatory syndrome	2017-05-09	criteria provided, single submitter	clinical testing