Submissions for variant NM_199242.3(UNC13D):c.1759C>T (p.Arg587Cys)

gnomAD frequency: 0.00021  dbSNP: rs148574729

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000697071	SCV000406664	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2018-01-12	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.
Invitae	RCV000697071	SCV000825661	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 587 of the UNC13D protein (p.Arg587Cys). This variant is present in population databases (rs148574729, gnomAD 0.03%). This missense change has been observed in individual(s) with UNC13D-related conditions (PMID: 28399723, 28748566, 32542393). ClinVar contains an entry for this variant (Variation ID: 325260). 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 cysteine 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.
GeneDx	RCV001753784	SCV001988442	uncertain significance	not provided	2022-04-09	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a patient with suspected bleeding disorder and in a patient with suspected HLH in published literature (Fager Ferrari et al., 2018; Gadoury-Levesque et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 32542393, 28399723)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263028	SCV002543137	uncertain significance	Autoinflammatory syndrome	2021-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265732	SCV002547757	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.1759C>T (p.Arg587Cys) results in a non-conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 238542 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00018 vs 0.0027), allowing no conclusion about variant significance. c.1759C>T has been reported in the literature as a non-informative heterozygous (second allele not specified) genotype in individuals undergoing workup for suspected inherited bleeding disorders/suspected Familial Hemophagocytic Lymphohistiocytosis (HLH) (example, Ferrari_2018, Gadoury-Levesque_2020, Leinoe_2017). 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. The following publications have been ascertained in the context of this evaluation (PMID: 28748566, 28399723, 32542393). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.