Submissions for variant NM_006949.4(STXBP2):c.1456G>A (p.Ala486Thr)

gnomAD frequency: 0.00004  dbSNP: rs199839827

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001131959	SCV001291605	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	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	RCV001131959	SCV001542865	uncertain significance	Familial hemophagocytic lymphohistiocytosis 5	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 486 of the STXBP2 protein (p.Ala486Thr). This variant is present in population databases (rs199839827, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with STXBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 893534). 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 STXBP2 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.
Ambry Genetics	RCV003246712	SCV003950269	uncertain significance	Inborn genetic diseases	2023-04-07	criteria provided, single submitter	clinical testing	The c.1456G>A (p.A486T) alteration is located in exon 17 (coding exon 17) of the STXBP2 gene. This alteration results from a G to A substitution at nucleotide position 1456, causing the alanine (A) at amino acid position 486 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.