Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001851543 | SCV002113639 | uncertain significance | not provided | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the SIAE protein (p.Phe404Ser). This variant is present in population databases (rs201877149, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autoimmune disease or biliary cirrhosis (PMID: 20555325, 22257840). ClinVar contains an entry for this variant (Variation ID: 1353). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SIAE function (PMID: 20555325). 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, |
RCV003155009 | SCV003844487 | uncertain significance | not specified | 2023-02-01 | criteria provided, single submitter | clinical testing | Variant summary: SIAE c.1211T>C (p.Phe404Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251456 control chromosomes. This frequency does not allow conclusions about variant significance. c.1211T>C has been reported in the literature in individuals with diseases of an autoimmune etiology such as SLE, Juvenile idiopathic arthritis, Primary Biliary Cirrhosis and in unaffected controls (example, Surolia_2010, Hirschfield_2012, Sevdali_2017). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with Autoimmune Disease, Susceptibility To, 6. At least one publication reports experimental evidence evaluating an impact on protein function (Surolia_2010). The most pronounced variant effect results in >50% of normal esterase activity with the authors characterizing it as esterase and secretion defective. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| OMIM | RCV000001418 | SCV000021568 | risk factor | Autoimmune disease, susceptibility to, 6 | 2010-07-08 | no assertion criteria provided | literature only |