Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000779149 | SCV000915660 | uncertain significance | Alpha-1-antitrypsin deficiency | 2017-05-19 | criteria provided, single submitter | clinical testing | The SERPINA1 c.875C>T (p.Thr292Ile) variant has been reported in two studies in a total of three individuals with alpha-1 antitrypsin deficiency, all with the variant in a compound heterozygous state (Zorzetto et al. 2008; Graham et al. 2015). All patients had reduced serum alpha-1 antitrypsin levels. Two of the compound heterozygous individuals also carried a known pathogenic missense variant; it is not clear if these individuals are related (Graham et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.0001 in the European (non-Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Thr292Ile variant is therefore classified as a variant on unknown significance but suspicious for pathogencity for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV000779149 | SCV003028099 | uncertain significance | Alpha-1-antitrypsin deficiency | 2021-08-13 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with isoleucine at codon 292 of the SERPINA1 protein (p.Thr292Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs745624643, ExAC 0.009%). This missense change has been observed in individuals with alpha-1-antitrypsin deficiency (PMID: 18515255, 29882371). ClinVar contains an entry for this variant (Variation ID: 632222). 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 SERPINA1 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. |
| Prevention |
RCV003413569 | SCV004114680 | uncertain significance | SERPINA1-related disorder | 2022-09-21 | criteria provided, single submitter | clinical testing | The SERPINA1 c.875C>T variant is predicted to result in the amino acid substitution p.Thr292Ile. This variant has been reported in the compound heterozygous state (with either the N or Z allele) in three individuals with reduced alpha-1-antitrypsin concentrations (Referred to as T268I in Zorzetto et al. 2008. PubMed ID: 18515255; Graham et al. 2015. PubMed ID: 26321041). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-94847250-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Baylor Genetics | RCV000779149 | SCV004203142 | uncertain significance | Alpha-1-antitrypsin deficiency | 2022-06-28 | criteria provided, single submitter | clinical testing |