ClinVar Miner

Submissions for variant NM_006949.4(STXBP2):c.1772C>A (p.Ala591Asp)

gnomAD frequency: 0.00032  dbSNP: rs150701487
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001050071 SCV001214159 uncertain significance Familial hemophagocytic lymphohistiocytosis 5 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 591 of the STXBP2 protein (p.Ala591Asp). This variant is present in population databases (rs150701487, gnomAD 0.1%). 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: 846703). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 RCV004526073 SCV005040200 uncertain significance not specified 2024-03-05 criteria provided, single submitter clinical testing Variant summary: STXBP2 c.1772C>A (p.Ala591Asp) 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 0.0001 in 251204 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STXBP2 causing Familial Hemophagocytic Lymphohistiocytosis (0.0001 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, c.1772C>A has not been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36510129). ClinVar contains an entry for this variant (Variation ID: 846703). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV004693516 SCV005192538 uncertain significance not provided criteria provided, single submitter not provided

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