Submissions for variant NM_199242.3(UNC13D):c.1820G>C (p.Arg607Pro)

dbSNP: rs377293829

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779232	SCV000915783	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2018-02-13	criteria provided, single submitter	clinical testing	The UNC13D c.1820G>C (p.Arg607Pro) variant has been reported in one study and is found in a compound heterozygous state in one proband with atypical familial hemophagocytic lymphohistiocytosis (Rohr et al. 2010). The proband exhibited cerebral vasculitis, hypogammaglobulinemia, recurrent respiratory infections, chronic hepatitis, and persistent splenomegaly. The proband's first hemophagocytic lymphohistiocytosis event was lethal at 34 years of age (Rohr et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000330 in the African population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg607Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000779232	SCV000955919	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 3	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 607 of the UNC13D protein (p.Arg607Pro). This variant is present in population databases (rs377293829, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of hemophagocytic lymphohistiocytosis (PMID: 20823128, 32542393; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632290). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt UNC13D protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects UNC13D function (PMID: 29549174). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001759472	SCV001986290	uncertain significance	not provided	2021-04-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with an additional UNC13D variant in patients with features of hemophagocytic lymphohistiocytosis in the literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in both cases (Rohr et al., 2010; Gadoury-Levesque et al., 2020); This variant is associated with the following publications: (PMID: 20823128, 29549174, 32542393)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263971	SCV002543144	uncertain significance	Autoinflammatory syndrome	2017-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265885	SCV002547755	likely pathogenic	Familial hemophagocytic lymphohistiocytosis	2022-05-05	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.1820G>C (p.Arg607Pro) results in a non-conservative amino acid change located in the MUN domain (IPR010439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 247550 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00011 vs 0.0027), allowing no conclusion about variant significance. c.1820G>C has been reported in the literature in compound heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis (Rohr_2010, Gadoury-Levesque_2020). These data indicate that the variant may be associated with disease. The variant caused a significant decrease in munc13-4 protein expression in HEK293T and HVS-T1 cells (Shibata_2018). Three ClinVar submitters have assessed the variant since 2014: all have classified it as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.