ClinVar Miner

Submissions for variant NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys) (rs28931570)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000431149 SCV000227088 likely pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148875 SCV000389660 pathogenic Alpha-1-antitrypsin deficiency 2017-04-27 criteria provided, single submitter clinical testing The SERPINA1 c.187C>T (p.Arg63Cys) missense variant, more commonly known as p.Arg39Cys or the protease inhibitor (PI) type I variant (PI*I), is widely reported in the literature. Across a selection of the available literature, the p.Arg63Cys variant has been identified in a compound heterozygous state with a known pathogenic variant in at least 156 individuals with alpha-1 antitrypsin deficiency (Baur et al. 1987; Seri et al., 1992; Mahadeva et al. 1999; Ferrarotti et al., 2007; Zorzetto et al., 2008; Carroll et al., 2011; Donato et al., 2012; Suh-Lailam et al. 2014; Duk et al.2016; Silva et al. 2016). The p.Arg63Cys variant is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. Mahadeva et al. (1999) performed an in vitro functional study and discovered the p.Arg63Cys variant protein is conformationally unstable and forms polymer chains, while the wild type SERPINA1 protein remains monomeric. The variant is thought to have a mild effect on the SERPINA1 protein and likely requires the contribution of a strongly pathogenic variant to cause disease. Based on the collective evidence, the p.Arg63Cys variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000431149 SCV000521230 likely pathogenic not provided 2016-10-11 criteria provided, single submitter clinical testing The R63C variant in the SERPINA1 gene, also referred to as the I allele, has been reported previously in association with autosomal recessive alpha-1-antitrypsin deficiency when present in the homozygous state or when in trans with another pathogenic variant (Graham et al., 1989; Bornhorst et al., 2013; Suh-Lailam et al., 2014). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports R63C was observed in 18/8600 (0.21%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The R63C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved, however in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R63C as a likely pathogenic variant.
Invitae RCV000148875 SCV000956623 likely pathogenic Alpha-1-antitrypsin deficiency 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 63 of the SERPINA1 protein (p.Arg63Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28931570, ExAC 0.2%). This variant has been observed in combination with another SERPINA1 variant in individuals affected with alpha 1-antitrypsin deficiency (PMID: 24713750, 22912357, 10194472, 21752289, 2606478). This variant is also known as Arg39Cys and the I allele in the literature. ClinVar contains entries for this variant (Variation ID: 17974, 219354). This variant has been reported to affect SERPINA1 protein polymerization and causes reduced secretion of the protein (PMID: 10194472). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000148875 SCV001251538 likely pathogenic Alpha-1-antitrypsin deficiency criteria provided, single submitter research The SERPINA1 c.187C>T (p.R63C) variant (also known as the I allele) is a mildly deficient variant. Alpha-1 antitrypsin deficiency has been reported in individuals homozygous for the SERPINA1 I allele, or if the I allele is present with a more severe SERPINA1 variant (i.e. SERPINA1 c.1096G>A, p.E366K, also known as the Z allele) (PMID: 2606478, 10194472; 22912357).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000431149 SCV001500625 likely pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
OMIM RCV000019575 SCV000039872 other PI I 2016-07-15 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148875 SCV000190619 likely pathogenic Alpha-1-antitrypsin deficiency 2014-06-01 no assertion criteria provided research
Department of Laboratory Medicine and Genetics,Trillium Health Partners Credit Valley Hospital RCV000148875 SCV000608304 pathogenic Alpha-1-antitrypsin deficiency 2014-12-08 no assertion criteria provided curation Reduced enzyme activity

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