Submissions for variant NM_199242.3(UNC13D):c.1772C>T (p.Pro591Leu)

gnomAD frequency: 0.00073  dbSNP: rs144852879

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000699531	SCV000406663	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699531	SCV000828246	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 591 of the UNC13D protein (p.Pro591Leu). This variant is present in population databases (rs144852879, 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 hemophagocytic lymphohistiocytosis (PMID: 33746956). ClinVar contains an entry for this variant (Variation ID: 325259). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000699531	SCV002496022	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2021-03-30	criteria provided, single submitter	clinical testing	UNC13D NM_199242.2 exon 20 p.Pro591Leu (c.1772C>T): This variant has not been reported in the literature but is present in 0.1% (78/68036) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-75835485-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:325259). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263027	SCV002543139	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000699531	SCV002816517	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-04-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001726115	SCV005392265	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Observed in the homozygous state in an individual with hemophagocytic lymphohistiocytosis (PMID: 33746956); 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: 33746956)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726115	SCV001963052	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726115	SCV001963635	uncertain significance	not provided		no assertion criteria provided	clinical testing