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

gnomAD frequency: 0.00137  dbSNP: rs28931570

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000431149	SCV000227088	likely pathogenic	not provided	2017-08-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the R63C variant impairs protein secretion by forming aberrant disulfide bonds (Ronzoni et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24713750, 29882371, 26987331, 24055113, 25637381, 21228398, 23632999, 27296815, 30487145, 31447099, 31589614, 2606478, 26647313, 34426522, 31980526)
Invitae	RCV000148875	SCV000956623	likely pathogenic	Alpha-1-antitrypsin deficiency	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the SERPINA1 protein (p.Arg63Cys). This variant is present in population databases (rs28931570, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with alpha 1-antitrypsin deficiency when in combination with the p.Glu366Lys (Pi*Z) variant. Individuals with this missense change and the p.Glu288Val (Pi*S) variant have been reported with mild or no deficiency of alpha 1-antitrypsin (PMID: 2606478, 10194472, 21752289, 22912357, 24713750). This variant is also known as Arg39Cys and the I allele. ClinVar contains an entry for this variant (Variation ID: 17974). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (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 Center for Human Genetics Tuebingen	RCV000431149	SCV001500625	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	SERPINA1: PS3, PS4, PP4:Moderate
Revvity Omics, Revvity	RCV000148875	SCV002019174	likely pathogenic	Alpha-1-antitrypsin deficiency	2021-06-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000148875	SCV002782052	likely pathogenic	Alpha-1-antitrypsin deficiency	2022-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000148875	SCV003844885	pathogenic	Alpha-1-antitrypsin deficiency	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: SERPINA1 c.187C>T (p.Arg63Cys) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251314 control chromosomes in the gnomAD database, including 1 homozygote. c.187C>T (also known as Arg39Cys and as I allele) has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (e.g. Mahadeva_1999, Carroll_2011, Donato_2012, Gupta_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits decreased stability, and forms aberrant disulphide bonds leading to reduced secretion of a1-antitrypsin (Mahadeva_1999, Jung_2004, Ronzoni_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as other. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390693	SCV004120316	likely pathogenic	SERPINA1-related condition	2024-01-17	criteria provided, single submitter	clinical testing	The SERPINA1 c.187C>T variant is predicted to result in the amino acid substitution p.Arg63Cys. This variant is also known as p.Arg39Cys and as the protease inhibitor (PI) type I variant (PI*I). It has been reported as a mild Alpha-1 antitrypsin deficiency variant that requires the presence of a second strong deficiency variant to cause disease (Amendola et al. 2015. PubMed ID: 25637381; Baur and Bencze. 1987. PubMed ID: 3496639; Mahadeva et al. 1999. PubMed ID: 10194472; Silva et al. 2016. PubMed ID: 27296815; Giacopuzzi et al. 2018. PubMed ID: 29882371). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We classify this variant as likely pathogenic.
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