ClinVar Miner

Submissions for variant NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys) (rs28929474)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 26
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195107 SCV000200303 risk factor Chronic obstructive pulmonary disease 2020-03-04 criteria provided, single submitter clinical testing SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiMZ) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). Large meta-analyses have reported odds ratios of 2.31-3.54 (OR= 2.31 95% CI [1.60-3.35], Hersh 2004, OR=3.54 95% CI [2.14-5.85] Topic 2012) developing COPD in individuals who are heterozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD. SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiZZ and historically reported as p.Glu342Lys) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). A large meta-analysis has reported an odds ratio of 42.42 [95% CI 4.41–332.55] (Topic 2012) for developing COPD in individuals who are homozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255454 SCV000230899 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000255454 SCV000321941 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing The E366K pathogenic variant in the SERPINA1 gene is commonly referred to as the Z variant or E342K by alternative nomenclature. The E366K pathogenic variant has been reported multiple times previously as this pathogenic variant accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (Hughes et al., 2014). The E366K variant removes a salt bridge to Lys290 and a hydrogen bond to Thr203, causing misfolding of the protein within the endoplasmic reticulum, which results in a lack of secretion from hepatocytes and a reduction of plasma AAT levels to 10-15% of normal (Hughes et al., 2014). The E366K variant is observed in 1,216/66,428 (1.8%) alleles from individuals of European (non-Finnish) background including multiple unrelated homozygous individuals in the ExAC dataset (Lek et al., 2016). The E366K variant is a non-conservative amino acid substitution occurring at a position that is conserved across species. We interpret E366K as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000148877 SCV000389647 pathogenic Alpha-1-antitrypsin deficiency 2016-06-14 criteria provided, single submitter clinical testing The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature and is also known as p.Glu342Lys, or more commonly, the Z allele. The p.Glu366Lys variant is the most common deficiency allele accounting for approximately ninety-five percent of clinically recognized cases of alpha-1 antitrypsin deficiency (AATD) (Stoller et al. 2014) and is reported at a frequency of 0.03030 in Utah residents with northern and western European ancestry from the 1000 Genomes Project. This frequency is high but consistent with disease prevalence. The severity of the AATD depends on genotype, with individuals who are homozygous for the p.Glu366Lys variant being at risk of developing both chronic obstructive pulmonary disease (COPD), including emphysema and liver disease. Homozygosity for the variant is a common cause of neonatal cholestasis. The p.Glu366Lys variant rarely leads to AATD-related symptoms in heterozygous individuals (American Thoracic Society 2003; Stoller et al. 2014). Individuals who are homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels and individuals who are heterozygous have approximately 61% (Calapoglu et al. 2009; Bornhurst et al. 2013). The decreased serum levels result in decreased functional activity of the AAT protein (Stoller et al. 2014). At least three studies have demonstrated that the low levels of serum AAT are a result of the p.Glu366Lys variant causing an accumulation of the protein in the endoplasmic reticulum of the hepatocyte with subsequent damage to the cells leading to liver disease (Dycaico et al. 1988; Lomas et al. 1992; Hughes et al. 2014). Bartlett et al. (2009) reported that the p.Glu366Lys variant is also a risk factor for liver disease in individuals with cystic fibrosis. Based on the collective evidence, the p.Glu366Lys variant is classified as pathogenic for alpha-1 antitrypsin deficiency.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000148877 SCV000538061 pathogenic Alpha-1-antitrypsin deficiency 2016-01-27 criteria provided, single submitter clinical testing In homozygous state this variant is the majorcause of severe alpha-1 antitrypsin deficiency (95%) and the mutant protein level is only 10-15% of the normal protein
Invitae RCV000148877 SCV000630386 pathogenic Alpha-1-antitrypsin deficiency 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 366 of the SERPINA1 protein (p.Glu366Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs28929474, ExAC 1.8%). This variant, also referred to as PI*Z allele or Z allele, is a well known cause of severe alpha-1 antitrypsin (AAT) deficiency in the literature (PMID: 15978931, 22426792, 23632999, 1889260). It is associated with an 80%-100% risk of developing emphysema when it is found in the homozygous state, and a 20-50% risk when it is found as a compound heterozygote with the S allele (PMID: 15978931, 22933512). This variant is also known as p.Glu342Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 17967). Experimental studies have shown that this missense change is five times less effective than the normal M allele as an inhibitor of neutrophil elastase and it forms polymers in the lung that can be chemoattractants for neutrophils, thereby increasing inflammation (PMID: 3500183, 9569237, 12034572). It has also been shown to alter the SERPINA1 protein natural conformation thereby contributing to the formation of polymers (PMID: 22735536, 25181470). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000623762 SCV000740918 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000148877 SCV000840071 pathogenic Alpha-1-antitrypsin deficiency 2017-06-05 criteria provided, single submitter clinical testing The c.1096G>A (p.Glu366Lys) variant in the SERPINA1 gene is a common pathogenic variant for alpha1-antitrypsin deficiency and is referred to the Z allele [PMID 6306478]. This variant has been reported in multiple patients with emphysema and liver disease [PMID 23858502, 19083091, 19444872, 26310624, 22912729]. This variant is common in the general population (up to 1.8%). Individual homozygous for this change have severe alpha-1 antitrypsin deficiency and are at risk to develop emphysema: plasma concentrations of alpha1-antitrypsin in homozygous individuals have been reported to be about 22% compared to normal [PMID 19083091]. Individual compound heterozygous for this change and another pathogenic variant (S allele or null allele) have variable alpha-1 antitrypsin deficiency depending on the allele in trans and are at risk to develop emphysema. This variant is classified as pathogenic. <BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant.
Fulgent Genetics,Fulgent Genetics RCV000762931 SCV000893353 pathogenic Chronic obstructive pulmonary disease; Alpha-1-antitrypsin deficiency 2018-10-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000148877 SCV000996188 pathogenic Alpha-1-antitrypsin deficiency 2018-08-21 criteria provided, single submitter clinical testing The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature. It is also referred to as p.Glu342Lys using alternate nomenclature, or is commonly referred to as the Z allele. Individuals homozygous for the p.Glu366Lys variant are at the highest risk for Alpha-1 antitripsin deficiency (AATD) and at risk of developing both chronic obstructive pulmonary disease (COPD), emphysema, liver disease and neonatal cholestasis. The homozygous ZZ allele genotype is a commonly recognized genetic cause of clinically recognized cases of AATD (PMID: 21960536). Individuals homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels while individuals who are heterozygous have approximately 61% (PMID: 19083091). It is present in the heterozygous state in the ExAC population database at a frequency of 1.17% (1410/120530) and in the homozygous state in 11 individuals. Based on the available evidence, this variant is classified as pathogenic.
Mendelics RCV000148877 SCV001139501 pathogenic Alpha-1-antitrypsin deficiency 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000148877 SCV001194095 pathogenic Alpha-1-antitrypsin deficiency 2019-12-26 criteria provided, single submitter clinical testing NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is classified as pathogenic in the context of alpha-1 antitrypsin deficiency. Sources cited for classification include the following: PMID 3264419, 18515255 and 3484754. Classification of NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255454 SCV001246283 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000148877 SCV001251536 pathogenic Alpha-1-antitrypsin deficiency criteria provided, single submitter research The SERPINA1 c.1096G>A, (p.E366K) variant (also known as the Z allele) is seen in 1.1% of the human population (gnomAD). It is reported as the most common pathogenic allele associated with alpha-1 antitrypsin deficiency (AATD). Individuals homozygous for the Z allele typically have severe AATD (PMID: 15978931).
OMIM RCV000019567 SCV000039864 other PI Z 2016-07-15 no assertion criteria provided literature only
OMIM RCV000019594 SCV000039892 other PI Z(AUGSBURG) 2016-07-15 no assertion criteria provided literature only
OMIM RCV000019595 SCV000039893 other PI Z(TUN) 2016-07-15 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148877 SCV000190621 pathogenic Alpha-1-antitrypsin deficiency 2014-06-01 no assertion criteria provided research
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000194811 SCV000223947 pathogenic FRAXE 2014-07-29 no assertion criteria provided clinical testing
GeneReviews RCV000148877 SCV000256612 pathogenic Alpha-1-antitrypsin deficiency 2014-05-01 no assertion criteria provided literature only
Baylor Genetics RCV000148877 SCV000328788 pathogenic Alpha-1-antitrypsin deficiency 2016-05-01 no assertion criteria provided clinical testing Our laboratory reported two molecular diagnoses in NLRC4 (NM_021209.4:c.512C>T) and SERPINA1 (NM_000295.4:c.1096G>A; NM_000295.4:c.863A>T; in trans) in an individual reported to have prematurity, congenital heart disease, hepatosplenomegaly, anemia, thrombocytopenia, direct hyperbilirubinemia, multi-organ system dysfunction, congenital ascites, cholestasis, polyuria, nonimmune hydrops fetalis and neonatal respiratory distress syndrome.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000148877 SCV000536708 pathogenic Alpha-1-antitrypsin deficiency 2016-06-10 no assertion criteria provided research
Department of Laboratory Medicine and Genetics,Trillium Health Partners Credit Valley Hospital RCV000148877 SCV000608296 pathogenic Alpha-1-antitrypsin deficiency 2014-12-08 no assertion criteria provided clinical testing Reduced enzyme activity, 10%-20% of normal
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000148877 SCV000733412 pathogenic Alpha-1-antitrypsin deficiency no assertion criteria provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000148877 SCV001142445 pathogenic Alpha-1-antitrypsin deficiency 2020-01-06 no assertion criteria provided curation NM_000295.4:c.1096G>A (p.Glu366Lys) was reported as p.Glu342Lys, or the Z allele or PI*Z. It has an allele frequency of 0.018 in European (no Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that that this variant plays as an inhibitor of neutrophil elastase and it forms polymers in the lung (PMID: 9569237), and alters the global structural dynamics of alpha-1-Antitrypsin (PMID: 25181470). The Glu342Lys accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 15978931). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3; BS1.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000255454 SCV001553787 pathogenic not provided no assertion criteria provided clinical testing The SERPINA1 p.E366K variant (referred to as the PI*Z allele) is the most common cause of Alpha-1 antitrypsin deficiency (AATD), with 95% of AATD-related disease reported to be caused by PI*ZZ (homozygosity for the PI*Z allele) (Stoller_2017_PMID:20301692). Homozygosity for the PI*Z variant results in decreased plasma concentrations of alpha-1-antitrypsin (~20%) compared to wildtype (Calapoğlu_2009_PMID:19083091). The variant was identified in dbSNP (ID: rs28929474) and ClinVar (classified as pathogenic by Illumina, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Invitae and 11 other laboratories). The variant was identified in control databases in 3176 of 282742 chromosomes (26 homozygous) at a frequency of 0.01123 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2369 of 129104 chromosomes (freq: 0.01835), European (Finnish) in 451 of 25112 chromosomes (freq: 0.01796), Other in 71 of 7220 chromosomes (freq: 0.009834), Ashkenazi Jewish in 87 of 10364 chromosomes (freq: 0.008394), Latino in 134 of 35410 chromosomes (freq: 0.003784), African in 62 of 24966 chromosomes (freq: 0.002483) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Glu366 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, functional studies have demonstrated that the PI*Z variant disrupts the native structure of the protein and results in increased polymerization and lack of functional protein (Hughes_2014_PMID:25181470; Lomas_1992_PMID:1608473). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.