Submissions for variant NM_199242.3(UNC13D):c.1216G>A (p.Gly406Ser)

gnomAD frequency: 0.00007  dbSNP: rs149099554

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000284415	SCV000406673	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2018-01-13	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.
Invitae	RCV000284415	SCV001496125	uncertain significance	Familial hemophagocytic lymphohistiocytosis 3	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 406 of the UNC13D protein (p.Gly406Ser). This variant is present in population databases (rs149099554, 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: 325265). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263029	SCV002543127	uncertain significance	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521125	SCV003681606	uncertain significance	Inborn genetic diseases	2021-07-20	criteria provided, single submitter	clinical testing	The c.1216G>A (p.G406S) alteration is located in exon 14 (coding exon 14) of the UNC13D gene. This alteration results from a G to A substitution at nucleotide position 1216, causing the glycine (G) at amino acid position 406 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.