Submissions for variant NM_199242.3(UNC13D):c.3160A>G (p.Ile1054Val)

gnomAD frequency: 0.00051  dbSNP: rs150952348

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000543692	SCV000638958	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1054 of the UNC13D protein (p.Ile1054Val). This variant is present in population databases (rs150952348, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 24916509). ClinVar contains an entry for this variant (Variation ID: 464458). 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 not expected to disrupt UNC13D 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.
Eurofins Ntd Llc (ga)	RCV000734026	SCV000862137	uncertain significance	not provided	2018-06-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000543692	SCV001282897	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263770	SCV002543182	uncertain significance	Autoinflammatory syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265792	SCV002547760	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: UNC13D c.3160A>G (p.Ile1054Val) results in a 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 0.00052 in 182704 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in UNC13D causing Familial Hemophagocytic Lymphohistiocytosis (0.00052 vs 0.0027), allowing no conclusion about variant significance. c.3160A>G has been reported in the literature as a double heterozygous genotype in combination with a missense variant c.272C>T (p.A91V) in the PRF1 gene in at-least one individual with Familial Hemophagocytic Lymphohistiocytosis (FHL) (Zhang_2014). The authors proposed a model of synergistic heterozygosity in FHL between two genes involved in cytotoxic lymphocyte degranulation. 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. ClinVar contains an entry for this variant (Variation ID: 464458). Based on the evidence outlined above, the variant was classified as uncertain significance.