14-94378610-C-T

Position:

• chr14-94378610-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1 PM5 PP5_Very_Strong BP4 BS1_Supporting

The NM_000295.5(SERPINA1):​c.1096G>A​(p.Glu366Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0159 in 1,614,142 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E366G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 33)
  • Exomes 𝑓: 0.016 (217 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:41 U:1 O:5
• Conservation: PhyloP100: 5.27

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_000295.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378609-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1989795.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 14-94378610-C-T is Pathogenic according to our data. Variant chr14-94378610-C-T is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 17967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94378610-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.011169165). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0122 (1851/152264) while in subpopulation NFE AF= 0.0206 (1399/68014). AF 95% confidence interval is 0.0197. There are 46 homozygotes in gnomad4. There are 899 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1096G>A	p.Glu366Lys	missense_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1096G>A	p.Glu366Lys	missense_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152146 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0111 AC: 2797 AN: 251360 Hom.: 19 AF XY: 0.0108 AC XY: 1472 AN XY: 135856

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.0162 AC: 23754 AN: 1461878 Hom.: 217 Cov.: 33 AF XY: 0.0155 AC XY: 11300 AN XY: 727242

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00414

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0122 AC: 1851 AN: 152264 Hom.: 46 Cov.: 33 AF XY: 0.0121 AC XY: 899 AN XY: 74440

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0147 Hom.: 25

Bravo AF: 0.0111

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0163 AC: 140

ExAC AF: 0.0116 AC: 1411

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0154

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:41 Uncertain:1 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:26 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 11, 2022	- -
Pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1096G>A;p.(Glu366Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 17967; PMID: 20301692; 29644095; 29618937; 26987331: 20301692) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 2904702, PMID: 19398551; PMID: 3500183) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Serpin domain) - PM1. The p.(Glu366Lys) was detected in trans with a pathogenic variant (PMID: 29882371; 26987331) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 29, 2022	ACMG classification criteria: PS3 supporting, PM3 very strong, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	Reduced enzyme activity, 10%-20% of normal -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -
Pathogenic, no assertion criteria provided	research	Genomics And Bioinformatics Analysis Resource, Columbia University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	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 -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 10, 2016	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 10, 2023	The SERPINA1 c.1096G>A (p.Glu366Lys) variant, also known as Gly342Lys or more commonly the Z allele, has been reported in the homozygous and compound heterozygous state in individuals with alpha1-antitrypsin deficiency and is reported as the most common pathogenic variant (Bornhorst JA et al., PMID: 23632999; Calapoğlu et al., PMID: 19083091; Stoller JK et al., PMID: 20301692; Stoller JK and Aboussouan LS, PMID: 21960536). While this variant rarely leads to alpha1-antitrypsin deficiency in heterozygous individuals, individuals that carry this variant in the heterozygous state have an increased risk for developing chronic obstructive pulmonary disease or liver disease (OR: 2.31-7.3; Hersh CP et al., PMID: 15454649; Strnad P et al., PMID: 30068662; Topic A et al., PMID: 22971141). This variant has been reported in the ClinVar database as a germline risk factor or pathogenic variant by many submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.8% in the European (non-Finnish) population which is not inconsistent with the prevalence of alpha1-antitrypsin deficiency (Brode SK et al., PMID: 22761482). The amino acid at this position is critical for protein function (Huang X et al., PMID: 27246852) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SERPINA1 function. In support of this prediction, functional studies show this variant leads to an accumulation of the protein leading to liver damage, indicating that this variant impacts protein function (Dycaico MJ et al., PMID: 3264419; Lomas DA et al., PMID: 1608473). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 (MONDO#0013282). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 3124 heterozygotes, 26 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 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 Serpin domain (DECIPHER, NCBI conserved domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as PI*Z, this the most common pathogenic allele causing alpha-1-antitrypsin deficiency (MONDO#0013282; ClinVar; GeneReviews; PMID: 15978931). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous indivdiuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2022	Variant summary: SERPINA1 (formerly known as PI) c.1096G>A (p.Glu366Lys; aka Glu342Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 251360 control chromosomes, predominantly at a frequency of 0.018 within the European subpopulation in the gnomAD database, including 17 homozygotes. Although the variant reaches polymorphic frequencies in Caucasians, this occurrence is consistent with the disease prevalence (see e.g. Stoller_2005, de Serres_2012, Blanco_2020). The variant, c.1096G>A (commonly known as the Z allele, or PI*Z allele) is reported as the most frequent alpha-1 antitrypsin deficiency allele, and individuals who are homozygous for the variant are at high risk for both lung- and liver disease, reportedly with 80-100% risk for developing emphysema (see e.g. Brantly_1991, Stoller_2005, Bornhorst_2013, Ferrarotti_2012, Stoller_2020, Tejwani_2021, Patel_2021). While nonsmoking heterozygotes are generally not considered to be at significantly increased risk for lung disease, smoking heterozygotes are at increased risk for COPD (Stoller_2020, Tejwani_2021). Several publications reported loss-of-function mechanism for the variant, i.e. homozygous individuals have a serum concentration of alpha-1 antitrypsin (AAT) that is approximately 10%-20% of normal, and the ability of the variant protein to inhibit neutrophil elastase is also decreased (e.g. Ogushi_1987, Bornhorst_2013). In addition, several studies also reported a gain-of-function mechanism for the variant, demonstrating that it can form (toxic) intracellular aggregates, and extracellular polymers with chemotactic properties for neutrophils, resulting in an exacerbated proinflammatory phenotype, especially in response to cigarette smoke (e.g. Elliott_1998, Parmar_2002, Alam_2014). 23 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 06, 2022	This individual is homozygous for a well documented variant known as the Z allele that causes a severe form of alpha-1 antitrypsin deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Mar 12, 2024	ACMG Criteria: PS3, PS4, PM3, PP1_S, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 21, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 05, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 30, 2022	PS3, PS4, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 366 of the SERPINA1 protein (p.Glu366Lys). This variant is present in population databases (rs28929474, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. 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. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17967). 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 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. -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2022	E366K is commonly referred to as the Z variant or E342K by alternative nomenclature; Accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (Hughes et al., 2014); Published functional studies demonstrate that 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); This variant is associated with the following publications: (PMID: 3495177, 23858502, 28146470, 2339709, 1608473, 22426792, 27959697, 29882371, 24055113, 27535533, 27153395, 26310624, 30068317, 29431110, 26771213, 6306478, 19083091, 22735536, 23837941, 22975760, 25637381, 19444872, 18340647, 19738092, 20981092, 22912729, 24082139, 21228398, 25181470, 27246852, 25738741, 2700304, 21067581, 29644095, 29083408, 26647313, 24328305, 30254761, 30068662, 30739910, 31028937, 31564432, 24592811, 32087139, 31447099, 31980526, 31216405, 34426522, 33144682, 33726816) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SERPINA1: PS3, PS4, PM5, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

FRAXE Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jul 29, 2014

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2017

The p.E366K pathogenic mutation (also known as c.1096G>A), located in coding exon 4 of the SERPINA1 gene, results from a G to A substitution at nucleotide position 1096. The glutamic acid at codon 366 is replaced by lysine, an amino acid with similar properties. This mutation comprises the common deficiency allele PI*Z. The resulting mutant protein polymerizes and aggregates in the endoplasmic reticulum of hepatocytes; in addition, the polymerized protein is resistant to degradation (Carrell RW et al. N. Engl. J. Med., 2002 Jan;346:45-53). Individuals with PI*Z/PI*Z have severe alpha-1-antitrypsin (AAT) deficiency with an increased risk for chronic obstructive pulmonary disease; whereas the risk of symptoms due to this mutation in other genotypes is dependent upon the second allele, serum AAT levels, and exposure to environmental risk factors (Köhnlein T et al. Am. J. Med., 2008 Jan;121:3-9; Stoller JK et al. GeneReviews. 2006 Oct 27 [Updated 2017 Jan 19]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

SERPINA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The SERPINA1 c.1096G>A variant is predicted to result in the amino acid substitution p.Glu366Lys. This variant has been well-documented to be pathogenic for autosomal recessive alpha-1 antitrypsin deficiency (see for example Table 3 of Dorschner et al. 2013. PubMed ID: 24055113). It is known as the Z allele using legacy nomenclature (http://www.ncbi.nlm.nih.gov/books/NBK1519/). We interpret this variant as pathogenic. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 06, 2020

ACMG classification criteria: PS3, PS4, PM3 -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Dec 16, 2021

- -

Alpha-1-antitrypsin deficiency;C1847014:COPD, severe early onset Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 31, 2020

SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous individuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -

Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 13, 2022

- -

PI Z(TUN) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI Z Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Chronic obstructive pulmonary disease Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

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. -

PI Z(AUGSBURG) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;D;D;D;D;D;D;D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D
Vest4		0.71
MPC		0.32
ClinPred		0.061	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28929474; hg19: chr14-94844947; COSMIC: COSV99054006; COSMIC: COSV99054006;