Submissions for variant NM_199242.3(UNC13D):c.1454C>T (p.Pro485Leu)

dbSNP: rs550974990

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221099	SCV001393123	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 485 of the UNC13D protein (p.Pro485Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs550974990, gnomAD 0.006%). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 29665027). ClinVar contains an entry for this variant (Variation ID: 949603). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490131	SCV004241421	uncertain significance	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.1454C>T (p.Pro485Leu) 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 2.4e-05 in 250150 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1454C>T has been reported in the literature in one individual affected with Familial Hemophagocytic Lymphohistiocytosis (Chen_2018). These 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 have been ascertained in the context of this evaluation (PMID: 29665027). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.