ClinVar Miner

Submissions for variant NM_001127701.1(SERPINA1):c.863A>T (p.Glu288Val) (rs17580)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000148878 SCV000328789 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.
CSER_CC_NCGL; University of Washington Medical Center RCV000148878 SCV000190622 pathogenic Alpha-1-antitrypsin deficiency 2014-06-01 no assertion criteria provided research
Department of Laboratory Medicine and Genetics,Trillium Health Partners Credit Valley Hospital RCV000148878 SCV000608331 pathogenic Alpha-1-antitrypsin deficiency 2014-12-08 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000148878 SCV000733413 pathogenic Alpha-1-antitrypsin deficiency no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000148878 SCV000536794 pathogenic Alpha-1-antitrypsin deficiency 2016-06-10 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000177031 SCV000228843 other not provided 2018-04-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762932 SCV000893354 pathogenic Chronic obstructive pulmonary disease; Alpha-1-antitrypsin deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000177031 SCV000568767 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The E288V pathogenic variant in the SERPINA1 gene is commonly referred to as the S variant or E264V by alternate nomenclature, and has been reported multiple times in association with partial alpha-1 antitrypsin deficiency (Curiel et al., 1989; Ferrarotti et al., 2012). Homozygosity for E288V does not appear to be associated with clinical disease, but this variant can be of clinical consequence when in the compound heterozygous state with the Z allele (E366K) (Curiel et al., 1989; Ferrarotti et al., 2012; Turino et al., 1996). The E288V variant 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). The E288V variant is observed in 4,641/126,702 (3.7%) alleles from individuals of non-Finnish European background, including multiple unrelated homozygous individuals, in large population cohorts (Lek et al., 2016). The E288V variant is a non-conservative amino acid substitution. We interpret E288V as a pathogenic variant.
GeneReviews RCV000148878 SCV000256613 pathogenic Alpha-1-antitrypsin deficiency 2014-05-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000148878 SCV000607335 not provided Alpha-1-antitrypsin deficiency no assertion provided phenotyping only 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.
Illumina Clinical Services Laboratory,Illumina RCV000148878 SCV000389650 pathogenic Alpha-1-antitrypsin deficiency 2016-06-14 criteria provided, single submitter clinical testing 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.
Invitae RCV000148878 SCV000630393 pathogenic Alpha-1-antitrypsin deficiency 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 288 of the SERPINA1 protein (p.Glu288Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs17580, ExAC 3%). 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 by 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). 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 an increased risk for emphysema. However, since this variant is associated with a much lower risk than other Pathogenic alleles, it has been classified as Pathogenic (low penetrance).
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000148878 SCV000538062 pathogenic Alpha-1-antitrypsin deficiency 2016-03-30 criteria provided, single submitter clinical testing 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/).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000148878 SCV000271304 not provided Alpha-1-antitrypsin deficiency 2015-08-06 no assertion provided clinical testing The p.Glu288Val variant (also called the S allele) in SERPINA1 is a risk allele for alpha-1 antitrypsin deficiency which can result in increased risk for COPD and other lung conditions; however, only when compound heterozygous with a second SERPINA1 variant (p.Glu366Lys; also called the Z allele) (Hutchison 1983, Turino 1996, Dahl 2005, Stoller 2005, Lee 2006, Ramos 2013). Compound heterozygosity of p.Glu288Val and p.Glu366Lys is estimated to increase the risk of emphysema by 20-50% (Stoller 2005).
OMIM RCV000019569 SCV000039866 other PI S 2016-07-15 no assertion criteria provided literature only

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