ClinVar Miner

Submissions for variant NM_000295.5(SERPINA1):c.875C>T (p.Thr292Ile)

gnomAD frequency: 0.00001  dbSNP: rs745624643
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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 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.
PreventionGenetics, part of Exact Sciences 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

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