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

gnomAD frequency: 0.00031  dbSNP: rs61761869

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000443069	SCV000343429	pathogenic	not provided	2017-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000443069	SCV000516540	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced alpha-1-antitrypsin secretion and a complete intracellular transport block (Fra et al., 2012; Poller et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as P369S or Mwurzburg allele using alternate nomenclature; This variant is associated with the following publications: (PMID: 31980526, 10234508, 27296815, 11474657, 31447099, 34426522, 22723858, 31661293, 21228398, 29882371)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000336993	SCV000630387	pathogenic	Alpha-1-antitrypsin deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 393 of the SERPINA1 protein (p.Pro393Ser). This variant is present in population databases (rs61761869, gnomAD 0.05%). This missense change has been observed in individuals with alpha-1-antitrypsin deficiency (AATD) (PMID: 18024524, 27296815). ClinVar contains an entry for this variant (Variation ID: 289135). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508, 27296815). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2784123, 10234508, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham 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.
Illumina Laboratory Services, 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.
Revvity Omics, Revvity	RCV000336993	SCV002020069	pathogenic	Alpha-1-antitrypsin deficiency	2022-02-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000336993	SCV002060278	uncertain significance	Alpha-1-antitrypsin deficiency	2021-10-01	criteria provided, single submitter	clinical testing	NM_000295.4(SERPINA1):c.1177C>T(P393S) is a missense variant classified as a variant of uncertain significance in the context of alpha-1 antitrypsin deficiency. P393S has been observed in cases with relevant disease (PMID: 19437508, 18515255, 10878477, 10234508, 27296815, 21474916, 19654085). Functional assessments of this variant are available in the literature (PMID: 22723858, 10234508). P393S has been observed in population frequency databases (gnomAD: NFE 0.05%). In summary, there is insufficient evidence to classify NM_000295.4(SERPINA1):c.1177C>T(P393S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Mendelics	RCV000336993	SCV002519713	pathogenic	Alpha-1-antitrypsin deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000336993	SCV002768009	pathogenic	Alpha-1-antitrypsin deficiency	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (81 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) with p.(Pro393Leu) having the highest allele count (14 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated reactive centre loop (RCL) within the Serpin domain (NCBI conserved domains; Pfam). (I) 0704 - Another missense variants comparable to the one identified in this case have limited previous evidence for pathogenicity. The p.(Pro393Leu) (alternatively known as P369L or MHeerlen) has previously been reported in at least 5 patients and has been suggested to result in extremely low AAT level and no liver disease (ClinVar; PMID: 26321041; 2784123; 27296815; 10234508). In addition, p.(Pro393His) has previously been reported in an adult female patient (compound heterozygote with the 'S' allele) suspected of having AATD however AAT serum level was normal (PMID: 31307431) and p.(Pro393Thr) was previously reported as pathogenic and as a variant of uncertain significance once each in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is also known as p.(Pro369Leu) in an alternative nomenclature or as the MWurzburg allele. It has previously been reported in at least 8 alpha-1-1-antitrypsin deficiency patients and is often referred to as a severe deficient allele (ClinVar; PMIDs: 27296815; 18024524; 18515255; 11474657; 19437508; 10878477). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro and in vivo functional studies have demonstrated that this variant results in intracellular transportation and secretion defects (PMID: 10234508; 22723858). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000443069	SCV004130295	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SERPINA1: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting
Baylor Genetics	RCV000336993	SCV004203113	pathogenic	Alpha-1-antitrypsin deficiency	2024-03-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000443069	SCV005414249	pathogenic	not provided	2024-02-13	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM5, PS3
PreventionGenetics, part of Exact Sciences	RCV003409418	SCV004114568	pathogenic	SERPINA1-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The SERPINA1 c.1177C>T variant is predicted to result in the amino acid substitution p.Pro393Ser. This variant has been reported to be pathogenic for autosomal recessive alpha1-antitrypsin deficiency (Giacopuzzi et al. 2018. PubMed ID: 29882371; Ortega et al. 2019. PubMed ID: 31661293). It is known as the M (Würzburg) allele in the literature. This variant is reported in 0.053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is reported as pathogenic.