Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000798837 | SCV000938472 | uncertain significance | Immunodeficiency 31B; Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome; Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency | 2018-11-21 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Met390 amino acid residue in STAT1. Other variant(s) that disrupt this residue have been observed in individuals with individuals with STAT1-related conditions (PMID: 24343863, 27114460), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with STAT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 390 of the STAT1 protein (p.Met390Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. |
| Ambry Genetics | RCV002537101 | SCV003582433 | uncertain significance | Inborn genetic diseases | 2021-11-24 | criteria provided, single submitter | clinical testing | The c.1168A>G (p.M390V) alteration is located in exon 14 (coding exon 12) of the STAT1 gene. This alteration results from an A to G substitution at nucleotide position 1168, causing the methionine (M) at amino acid position 390 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at the same codon, p.M390T (c.1169T>C) and p.M390I (c.1170G>A), have been reported in heterozygous individuals affected with mucocutaneous candidiasis (Mizoguchi, 2014; Toubiana, 2016). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Rady Children's Institute for Genomic Medicine, |
RCV003336192 | SCV004046277 | likely pathogenic | STAT1-Related Immunodeficiency | criteria provided, single submitter | clinical testing | Different missense variants affecting the same amino acid residue (c.1169T>C, p.Met390Thr; c.1170G>A, p.Met390Ile) have been previously reported as de novo or of unknown inheritance in individuals with STAT1-related disorders (PMID: 24343863, 21714643). The STAT1 gene is highly constrained (Z-score= 5.15 and pLI = 1), which suggests it is intolerant to variation. The c.1168A>G (p.Met390Val) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1168A>G (p.Met390Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1168A>G (p.Met390Val) variant is classified as Likely Pathogenic. |