ClinVar Miner

Submissions for variant NM_000295.5(SERPINA1):c.1177C>T (p.Pro393Ser) (rs61761869)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000443069 SCV000343429 pathogenic not provided 2017-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000443069 SCV000516540 pathogenic not provided 2015-03-27 criteria provided, single submitter clinical testing The P393S variant in the SERPINA1 gene was first reported (reported as P369S and the Mwurzburg allele due to alternative nomenclature) in the heterozygous state in a patient with decreased serum alpha-1-antitrypsin levels but no evidence of lung or liver disease (Poller et al., 1999). It was later reported in a patient with cholestasis and intrahepatic alpha-1-antitrypsin accumulation who was a compound heterozygote for the P393S variant and an S variant allele (Seixas et al., 2001). The P393S substitution was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P393S 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 conserved across species. Functional studies show that the P393S variant results in intracellular accumulation and reduced secretion of alpha1-antitrypsin (Poller et al., 1999; Fra et al., 2012). We interpret P393S as a pathogenic variant.
Invitae RCV000336993 SCV000630387 pathogenic Alpha-1-antitrypsin deficiency 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 393 of the SERPINA1 protein (p.Pro393Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs61761869, ExAC 0.04%). This variant has been reported in the literature as a compound heterozygous in individuals affected with alpha-1-antitrypsin deficiency (AATD) (PMID: 27296815, 18024524). This variant is also known in the literature as MWurzburg and as Pro369Ser. ClinVar contains an entry for this variant (Variation ID: 289135). Experimental studies have shown that this missense change causes a dramatic reduction of the levels of SERPINA1 enzyme levels in vitro (PMID: 10234508, 27296815) and in vivo (PMID: 10234508). A different missense substitution at this codon (p.Pro393Leu) has been determined to be pathogenic (PMID: 2784123, 10234508, 27296815). This suggests that the proline residue is critical for SERPINA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000336993 SCV000711354 likely pathogenic Alpha-1-antitrypsin deficiency 2017-05-13 criteria provided, single submitter clinical testing The p.Pro393Ser variant in SERPINA1 (MWurzburg allele) has been reported in at l east 5 individuals with SERPINA1-related phenotypes, including alpha-1-antitryps in deficiency (AATD), asthma, elevated transaminases, and intrahepatic inclusion s (Poller 1999, Sexias 2001, Medicina 2009, Silva 2016, and Denden 2009). Three of these individuals were heterozygous, while 2 individuals with liver phenotype s were compound heterozygous. The variant segregated in at least 1 family member with low levels of alpha-1-antritrypsin and 2 members of 1 family with asthma ( Poller 1999, Denden 2009). In vitro and in vivo functional studies provide some evidence that the p.Pro393Ser variant may impact protein function; however, thes e types of assays may not accurately represent biological function (Poller 1999, Fra 2012). This variant has also been identified in 29/66728 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs61761869); however, this frequency is low enough to be consistent with a r ecessive carrier frequency. Furthermore, a different variant at the same positio n (p.Pro393Leu) has been classified as pathogenic by our laboratory, supporting that a change at this position may not be tolerated. In summary, although additi onal studies are required to fully establish its clinical significance, the p.Pr o393Ser variant is likely pathogenic.
Counsyl RCV000336993 SCV000800690 uncertain significance Alpha-1-antitrypsin deficiency 2018-04-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336993 SCV000915659 likely pathogenic Alpha-1-antitrypsin deficiency 2018-08-17 criteria provided, single submitter clinical testing The SERPINA1 c.1177C>T (p.Pro393Ser) variant, also referred to as Pi-M(Wurzburg), has been identified in a compound heterozygous state in three patients with alpha-1 antitrypsin deficiency (AATD) (Seixas et al. 2001; Medicina et al. 2009; Zorzetto et al. 2008). Control data are unavailable for this variant, which is reported at a frequency of 0.000513 in the European (non-Finnish) population of the Genome Aggregation Database. Poller et al. (1999) performed in vitro and in vivo functional studies and demonstrated that the p.Pro393Ser variant had defective intracellular transport and secretion into the bloodstream compared to the wild type AAT protein. The Pro393 residue is predicted to form part of a critical domain of the AAT protein. Based on the evidence, the p.Pro393Ser variant is classified as likely pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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