ClinVar Genomic variation as it relates to human health

The variant c.863A>T (p.Glu288Val) is also called the “S” allele and, together with the “Z” allele, represent the most common disease-causing variants in alpha1-Antitrypsin. The S allele has been shown to cause reduced cellular secretion of alpha 1AT because the newly synthesized S-type alpha 1AT protein is degraded intracellularly prior to secretion (Curiel et al., 1989). This variant has been well studied in the literature and is predicted pathogenic by multiple computational algorithms. In summary, this variant meets our criteria for pathogenic, but only in combination with the Z allele. The SS homozygous genotype is not reported to be associated with disease, and thus, does not warrant prenatal diagnosis. The S allele is only concerning when in combination with the Z allele (GeneReviews: Stoller et al., http://www.ncbi.nlm.nih.gov/books/NBK1519/).

The SERPINA1 c.863A>T, (p.E288V) variant (also known as the S allele) is seen in 2.3% of the human population (gnomAD). This allele is reported to be pathogenic, which results in a deficient protein. Alpha-1 antitrypsin deficiency typically manifests clinically when the S allele is seen in the compound heterozygous state with another pathogenic allele (i.e. the Z allele) (PMID: 20301692).

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-1-1-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 glutamic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (6606 heterozygotes, 143 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 superfamily domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well-studied pathogenic variant in AAT deficiency, also known as the S allele, and is only disease causing when in trans with another pathogenic allele. Homozygous and heterozygous S allele carriers do not present with symptoms (ClinVar, PMID: 15978931). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The S allele has previously been shown to result in intracellular protein degradation (PMID: 15978931). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) – Supporting pathogenic, (I) - Information, (SB) – Supporting benign

Results in reduced cellular secretion of alpha-1 antitrypsin as the S-type alpha-1 antitrypsin protein is degraded intracellularly prior to secretion (Curiel et al., 1989; Ferrarotti et al., 2012); 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: 24055113, 22975760, 20981092, 26672964, 25637381, 2567291, 8970361, 22426792, 27535533, 27153395, 27959697, 22933512, 29882371, 29232161, 31447099, 31980526)

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 288 of the SERPINA1 protein (p.Glu288Val). This variant is present in population databases (rs17580, gnomAD 4%), and has an allele count higher than expected for a pathogenic variant. This variant, also referred as PI*S allele or S allele, is a common variant associated with alpha-1 antitrypsin deficiency (AATD). Individuals with AATD have an increased risk for developing pulmonary disease such as chronic obstructive pulmonary disease (COPD) or emphysema. This variant is reported to confer an emphysema risk of 20-50% in individuals when present with a pathogenic PI*Z allele or Z allele (p.Glu366Lys), while in individuals when present as a homozygote or heterozygote it does not confer a risk (PMID: 1889260, 15978931, 22933512, 23632999). This variant is also known as p.Glu264Val in the literature. ClinVar contains an entry for this variant (Variation ID: 17969). 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 variant results in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro (PMID: 2567291), and causes lower expression as well as secretion in blood (PMID: 2567291, 22426792). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the SERPINA1 gene, it has been classified as Pathogenic (low penetrance).

This sequence change in SERPINA1 is predicted to replace glutamic acid with valine at codon 288, p.(Glu288Val). The glutamic acid residue is highly conserved (86/86 vertebrates, UCSC). There is a large physicochemical difference between glutamic acid and valine. This variant is common in the European (non-Finnish) population with a minor allele frequency of 3.7% (4,738/129,176 alleles, including 117 homozygotes) in this population in the population database gnomAD v2.1. SERPINA1, in which the variant was identified, is a gene known to have two pathogenic missense variant alleles- PI*S (this variant) and PI*Z (c.1096G>A, p.Glu366Lys), that are responsible for the majority of cases of alpha-1-antitrypsin deficiency when present as homozygous (PI*ZZ) or compound heterozygous (PI*SZ) genotypes; truncating variants are also rarely present (PMID: 20301692). PI*SZ compound heterozygotes also have reduced serum alpha-1-antitrypsin levels, which is highly specific for alpha-1-antitrypsin deficiency (PMID: 22426792, 23632999, 15994391). In silico modelling and in vitro assays using human blood monocytes and mouse fibroblasts showed that the mutant protein is more susceptible to intracellular polymerisation and degradation leading to reduced secretion when compared to the wildtype protein; other studies using purified variant protein from homozygotes demonstrated a small but significant decrease in protease inhibitory activity (PMID: 3257660). Together, these indicate that this variant impacts protein function. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3, PS3_Supporting.

The c.863A>T (p.Glu288Val) variant, which is also reported as p.Glu264Val or the S allele, is usually of clinical consequence only in the compound heterozygous state with another pathogenic allele that results in concentrations of alpha-1 antitrypsin (AAT) that fall below the protective threshold of 57 mg/dL (Stoller et al. 2014). The p.Glu288Val variant in a compound heterozygous state is not usually associated with a high risk for liver disease, though some individuals may be at an increased risk for lung disease (Turino et al. 1996). Individuals who are homozygous for the p.Glu288Val variant do not appear to be at an increased risk for clinical disease and often do not show any clinical symptoms (Ferrarotti et al. 2012). Curiel et al. (1989) demonstrated that the p.Glu288Val variant results in intracellular degradation of AAT protein prior to secretion. The p.Glu288Val variant is reported at a frequency of 0.10577 in the Puerto Ricans from Puerto Rico population in the 1000 Genomes Project. This allele frequency is high but is consistent with estimates of disease prevalence and mild clinical presentation. Based on the evidence, the p.Glu288Val variant is classified as pathogenic for alpha-1 antitrypsin deficiency.

PS3, PS4, PM3, PP3

The SERPINA1 c.863A>T variant is classified as PATHOGENIC (PS3, PS4, PM3) The SERPINA1 c.863A>T variant is a single nucleotide change in exon 3/5 of the SERPINA1 gene, which is predicted to change the amino acid glutamic acid at position 288 in the protein to valine. This variant has been identified in many individuals with Alpha-1-antitrypsin deficiency (PS4), in compound heterozygous state with another pathogenic allele (PM3). Well-established functional studies show a deleterious effect of this variant (PMID:2567291) (PS3). The variant has been reported in dbSNP (rs17580) and has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17969, HGMD: CM890097).

Variant summary: SERPINA1 c.863A>T (p.Glu288Val) results in a non-conservative amino acid change in the encoded protein sequence and is also known as the PI*S allele/S allele/p.Glu264Val in the literature. 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 0.023 in 251480 control chromosomes in the gnomAD database, including 131 homozygotes. This variant is one of the two most frequent deficiency alleles and is a common variant associated with alpha-1 antitrypsin deficiency (AATD). The variant is reported to confer a 20-50% emphysema risk in individuals when present with the pathogenic PI*Z allele or Z allele (p.Glu366Lys), while in does not confer a risk in individuals when present as a homozygote or heterozygote (Review: Stoller_2005). Experimental studies have shown this variant to result in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro, which causes lower expression as well as secretion in blood (Curiel_1999) . 21 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Most submitters report the variant as pathogenic or risk allele/low penetrance. Based on the evidence outlined above, the variant was classified as pathogenic - low penetrance.

The c.863A>T (p.E288V) alteration is located in exon 3 (coding exon 2) of the SERPINA1 gene. This alteration results from a A to T substitution at nucleotide position 863, causing the glutamic acid (E) at amino acid position 288 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 2.335% (6606/282868) total alleles studied. The highest observed frequency was 3.668% (4738/129176) of European (non-Finnish) alleles. This mutation comprises the common deficiency allele PI*S. The risk of alpha-1-antitrypsin (AAT) deficiency symptoms due to this mutation is dependent upon the genotype, serum AAT levels, and exposure to environmental risk factors (K&ouml;hnlein, 2008; Stoller, 1993). In vitro studies demonstrate that this mutant allele results in reduced AAT levels due to intracellular degradation and decreased secretion of the protein (Curiel, 1989). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

SERPINA1: PP4:Strong, PS4, PS3:Moderate, PP3

The SERPINA1 c.863A>T variant is predicted to result in the amino acid substitution p.Glu288Val. This variant is a well-documented pathogenic allele resulting in functionally-deficient alpha-1 antitrypsin (AAT) protein (also known as the S allele in the legacy nomenclature; Abboud et al. 2011. PubMed ID: 23776367, reported as Glu264Val; GeneReviews, Stoller et al. 2023. PubMed ID: 20301692). This particular variant is observed at a high frequency in unaffected individuals, and only expected to cause disease when found in trans (on the opposite chromosome) with a second more damaging variant in this gene (Ferrarotti et al. 2012. PubMed ID: 22426792). This variant is interpreted as pathogenic.

The SERPINA1 p.Glu288Val variant, also known as the S allele, is a common variant known to be associated with alpha-1 antitrypsin deficiency, which can result in increased risk for emphysema and COPD when found in the compound heterozygous state with another pathogenic SERPINA1 variant. The variant was identified in dbSNP (ID: rs17580), LOVD 3.0 (classified as pathogenic) and ClinVar (classified as pathogenic by 11 submitters). The variant was identified in control databases in 6606 of 282868 chromosomes (143 homozygous) at a frequency of 0.023354 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 4738 of 129176 chromosomes (freq: 0.03668), Other in 236 of 7222 chromosomes (freq: 0.03268), Latino in 1074 of 35440 chromosomes (freq: 0.0303), Ashkenazi Jewish in 144 of 10370 chromosomes (freq: 0.01389), European (Finnish) in 210 of 25122 chromosomes (freq: 0.008359), African in 203 of 24968 chromosomes (freq: 0.00813) and East Asian in 1 of 19954 chromosomes (freq: 0.00005); it was not observed in the South Asian population. This variant is reported to confer an emphysema risk by 20-50% in individuals when present with a pathogenic Z allele (p.Glu366Lys) but does not confer risk when present as a homozygote or heterozygote (Brantly_1991_PMID:1889260, Stoller_1995_PMID:15978931, de Serres_2012_PMID:22933512, Bornhorst_2013_PMID:23632999). In a meta-analysis aggregating data from six studies, the odds ratio (OR) for COPD in PI SZ compound heterozygotes compared with PI MM (normal) individuals was significantly increased (Dahl_2005_PMID: 15994391). The p.Glu288 residue is 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 however 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5' splice site, however RNA analysis has not confirmed this. Functional studies of the variant have shown to cause reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro and to cause lower expression as well as secretion of alpha-1 antitrypsin in blood samples (Curiel_1989_PMID: 2567291; Ferraroti_2012_PMID:22426792). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

Susceptibility to severe coronavirus disease (COVID-19)

Variant classified as Uncertain Risk Allele. SERPINA1 c.863A>T (p.Glu288Val, commonly known S allele or PiMS and historically reported as p.Glu264Val) 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 (3.7% Genome Aggregation Database (gnomAD); rs17580) and is present in ClinVar (ID:17969). A large meta-analysis has reported an odds ratio of 1.19 [95% CI 1.02-1.38] for developing COPD in individuals who are heterozygous for this variant (Dahl 2005). In vitro functional studies provide some evidence that p.Glu288Val variant may impact the protein function (Fregonese 2008). In summary, this variant is an uncertain risk factor for COPD.

Variant interpreted as Pathogenic and reported on 09-08-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-03-2012 by Lab or GTR ID Pathway Genomics. Variant interpreted as Pathogenic and reported on 05-10-2010 by Counsyl. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.