Submissions for variant NM_199242.3(UNC13D):c.2039G>A (p.Arg680Gln)

dbSNP: rs201324352

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037365	SCV001200775	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 680 of the UNC13D protein (p.Arg680Gln). This variant is present in population databases (rs201324352, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with UNC13D-related conditions. ClinVar contains an entry for this variant (Variation ID: 836278). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689963	SCV005185194	uncertain significance	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.2039G>A (p.Arg680Gln) results in a 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 1.6e-05 in 250012 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2039G>A has been reported in the literature in at least one individual affected with hemophagocytic lymphohistiocytosis (example: Xinh_2021). This report does 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 publication has been ascertained in the context of this evaluation (PMID: 34339548). ClinVar contains an entry for this variant (Variation ID: 836278). Based on the evidence outlined above, the variant was classified as uncertain significance.