The SERPINA1 NM_001127701.1:c.1096G>A (NP_001121173.1:p.(Glu366Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.SERPINA1 encodes alpha-1 antitrypsin, a serine protease inhibitor made mainly in the liver that helps control enzymes such as elastase, trypsin, and thrombin. Changes in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. No established role in cancer is indicated.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: missense REVEL score 0.686 exceeds the PP3 supporting threshold of 0.644.
No benign criterion marked as applied in the recorded assessment.
VUS: PP3 (supporting) is the only applied criterion and does not satisfy a generic ACMG Likely Pathogenic, Pathogenic, Likely Benign, or Benign combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 25,605 / 1,614,142 alleles. Recorded AF 0.0158629. Recorded homozygote count 263.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009721920486639148, 179/18412 alleles, homozygotes = 1).
Recorded REVEL score: 0.686. Refer to the recorded PP3/BP4 rationale for interpretation.
45 Pathogenic · 1 risk factor · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 8 not met · 15 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers SERPINA1 in this case; the generic ACMG/AMP rules supplied for this interpretation govern.
The exact queried variant is NM_001127701.1:c.1096G>A (p.Glu366Lys). Literature discussing the SERPINA1 E342K/Z variant was not treated as evidence for this exact variant.
PP5 and BP6 were not triggered because the exact-variant ClinVar audit reports zero expert-panel submissions.
PP3 is met at supporting strength from the applicable missense REVEL path; BP4 is not met because the same REVEL score is above the benign threshold.
SpliceAI and BayesDel are not counted for these missense PP3/BP4 decisions.
Population data do not support BA1 or PM2: the variant is present at approximately 1.1% to 1.6% overall, below 5% but far above 0.01%.
BS1 is not assigned because SERPINA1-related disease has adult-onset and variable-penetrance features and no disease-specific maximum-credible-frequency calculation is available.
BS2 is not assessed because aggregate homozygote counts do not document healthy adults with full penetrance expected at an early age.
No criteria match.
The variant is a missense SNV, NM_001127701.1:c.1096G>A (NP_001121173.1:p.(Glu366Lys)); therefore the applicable generic computational path is REVEL only. REVEL is 0.686, meeting the supplied PP3 supporting threshold of >= 0.644 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997). SpliceAI max delta 0.00 and BayesDel 0.191219 are not used for PP3: SpliceAI is outside the missense path and no generic ACMG-strength calibration is established for BayesDel.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is NP_001121173.1:p.(Glu366Lys), and ClinVar reports this same nucleotide variant as Pathogenic, but no different nucleotide change producing the same amino-acid substitution is documented in the available evidence. Therefore the same-amino-acid-change requirement for PS1 is not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
SERPINA1 has no VCEP domain table in vcep_materials.json. The available cancerhotspots.org search reports no statistically significant hotspot at E366, and the evidence bundle provides no established critical functional domain at residue 366 with absent benign variation. The generic PM1 requirement is therefore not met on the available evidence.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met. The generic supporting threshold supplied for PM2 is allele frequency <=0.0001. This variant is substantially more frequent than that threshold in gnomAD v4.1 all-comers (0.0158629), gnomAD v2.1 all-comers (0.0112329), gnomAD v2.1 non-cancer exomes (0.0110197), and gnomAD v3.1 non-cancer genomes (0.0119816), and homozygotes are observed in each reported dataset.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The queried missense change is p.Glu366Lys. The available same-residue comparator search identified zero candidates and no previously established pathogenic alternative missense change at residue 366. PM5 is not met.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar reports no expert-panel submission for this exact variant; the available record is based on ordinary laboratory submissions and therefore cannot trigger PP5. Reviewed papers discussing SERPINA1 pathogenic variants concern other variants, especially E342K/Z, rather than the queried p.Glu366Lys variant.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The generic rule requires an allele frequency above 5% in ESP, 1000 Genomes, or ExAC. The observed frequency is 0.0158629 (1.58629%) in gnomAD v4.1 all-comers and 0.0112329 (1.12329%) in gnomAD v2.1 all-comers, with maximum reported population frequencies of 0.0193938 and 0.0183495, respectively; these are below 0.05. The non-cancer subsets are also below the threshold: 0.0110197 in gnomAD v2.1 non-cancer exomes and 0.0119816 in gnomAD v3.1 non-cancer genomes.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
The variant is a missense SNV, so BP4 must be assessed through the generic REVEL path only. REVEL is 0.686, which is above the supplied BP4 supporting cutoff of <= 0.29 and therefore does not support a benign computational effect. The SpliceAI max delta of 0.00 is not applicable to BP4 for this missense variant, and BayesDel has no established generic ACMG-strength calibration.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar reports zero expert-panel submissions for this exact variant, and the available ordinary laboratory submissions are not eligible to trigger BP6. No exact-variant reputable benign report was verified in the reviewed literature.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PS2 cannot be assessed because the available evidence does not establish that NM_001127701.1:c.1096G>A is de novo in an affected proband, does not confirm both maternity and paternity, and does not document absence of a family history. A ClinVar submission records paternal origin, but that single field is not confirmation of paternity and provides no maternity confirmation or de novo family-study details.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3 cannot be assessed because the available functional studies do not test the queried SERPINA1 NM_001127701.1:c.1096G>A (p.Glu366Lys, E366K) variant. PMID:25738741 evaluates wild-type and the distinct Z variant E342K using in vitro polymerization assays, and PMID:27246852 evaluates E342K and related residue-342 substitutions using recombinant folding, protease-inhibition, stability, and structural assays; neither source provides variant-specific evidence for E366K. Therefore, the required well-established functional evidence for a damaging effect on this variant is absent from the reviewed sources.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The governing ACMG/AMP PS4 rule requires a significantly increased prevalence in affected individuals compared with controls; its Note 1 specifies OR or RR >5.0 with a confidence interval excluding 1.0. The reviewed literature packet identified papers triaged for PS4, but verification of the available abstracts/full-text extracts found no exact NM_001127701.1:c.1096G>A (p.Glu366Lys) case-control counts, affected-carrier frequency, or matched-control frequency. gnomAD v4.1 reports the variant at AF 0.0158629 overall and 0.0193938 in European non-Finnish individuals, but no affected-case frequency is available, so an OR and 95% CI cannot be computed. Numeric comparison: no case-control OR/RR value is available, therefore an inequality such as OR > 5.0 cannot be evaluated.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
Not assessed: the available evidence does not document that NM_001127701.1:c.1096G>A is in trans with a pathogenic variant in an affected proband, nor does it establish the inheritance mode or parental phase required to determine whether the recessive PM3 rule applies.
For recessive disorders, detected in trans with a pathogenic variant
PM6 cannot be assessed because no case-level evidence shows that the variant was assumed to be de novo. The available ClinVar record contains a paternal-origin entry, but it does not document an assumed de novo event, the affected proband's phenotype, or testing of either parent sufficient to support this criterion.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because the available evidence does not identify affected family members carrying the variant, does not provide informative meioses or segregation counts, and does not show co-segregation in a family with SERPINA1-related disease. The ClinVar classification and general literature extracts do not supply variant-specific family segregation data.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The variant is missense and is common in population databases (gnomAD v4.1 AF 0.0158629; 25,605/1,614,142 alleles), but the available evidence does not provide a gene-level benign-missense rate or establish that missense variants are a common SERPINA1 disease mechanism using a criterion-appropriate dataset. The two required PP2 components cannot be assessed reliably.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing ACMG/AMP PP4 rule requires a patient's phenotype or family history highly specific for a disease with a single genetic etiology. The supplied case evidence does not provide a patient phenotype, family history, or a documented phenotype-to-disease match for this variant, so specificity cannot be judged.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 is not assessed from the generic 1% default alone. The variant frequency exceeds 1% in gnomAD v2.1 and v4.1 overall and is highest in European (non-Finnish) participants, but SERPINA1-related alpha-1-antitrypsin deficiency is an adult-onset, variably penetrant disorder. A maximum-credible-frequency calculation requires explicit disease prevalence, penetrance, allelic heterogeneity, and inheritance inputs that are not supplied here; therefore the frequency cannot be concluded to be greater than expected for this disorder under the generic rule.
Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not assessed. gnomAD reports homozygotes for this variant, including 263 in gnomAD v4.1 all-comers, 26 in gnomAD v2.1 all-comers, 18 in gnomAD v2.1 non-cancer exomes, and 45 in gnomAD v3.1 non-cancer genomes. However, these aggregate population counts do not establish that a named healthy adult individual carried the variant, nor do they establish full penetrance at an early age, which are required by the generic BS2 definition.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BS3 cannot be assessed because the available functional studies do not test the queried SERPINA1 NM_001127701.1:c.1096G>A (p.Glu366Lys, E366K) variant. PMID:25738741 evaluates wild-type and the distinct Z variant E342K in polymerization assays, while PMID:27246852 evaluates E342K and related residue-342 substitutions in folding, protease-inhibition, stability, and structural assays; neither source demonstrates preserved function or normal splicing for E366K. Thus, no well-established benign functional result is available for this variant.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BS4 cannot be assessed because the available evidence does not identify affected relatives who lack the variant, does not provide a pedigree or non-segregation count, and does not establish that the observed phenotype is familial rather than a phenocopy or due to another pathogenic variant. No variant-specific family non-segregation data are reported.
Lack of segregation in affected members of a family.
The available evidence does not establish that SERPINA1 disease is caused primarily by truncating variants. It includes general descriptions of null alleles and loss of function, but does not provide a validated gene-level comparison showing that truncating variants predominate over missense disease alleles. BP1 therefore cannot be assessed reliably.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Not assessed: the available evidence does not document the variant in trans with a pathogenic variant in an affected proband with a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing ACMG/AMP BP5 rule requires that the variant be found in a case with an alternate molecular basis for disease. No case-level evidence identifying an alternate molecular diagnosis was supplied for this variant, so BP5 cannot be evaluated.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001127701.1:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_001121173.1:p.(Glu366Lys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for SERPINA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001127701.1:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_001121173.1:p.(Glu366Lys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for SERPINA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001127701.1:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_001121173.1:p.(Glu366Lys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for SERPINA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001127701.1:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_001121173.1:p.(Glu366Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for SERPINA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in SERPINA1, mapped onto the exon structure of NM_001127701.1. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)22885 / 1,180,016 | 0.019248 hom |
| European (Finnish)1185 / 64,030 | 0.0199 hom |
| Remaining individuals757 / 62,508 | 0.0124 hom |
| Ashkenazi Jewish278 / 29,606 | 0.0094 |
| Amish7 / 910 | 0.00771 hom |
| Admixed American280 / 60,028 | 0.0047 |
| African/African American196 / 75,012 | 0.00261 hom |
| Middle Eastern5 / 6,062 | 0.00082 |
| South Asian12 / 91,086 | 0.00013 |
| European (non-Finnish)2369 / 129,104 | 0.01823 hom |
| European (Finnish)451 / 25,112 | 0.0183 hom |
| Remaining individuals71 / 7,220 | 0.0098 |
| Ashkenazi Jewish87 / 10,364 | 0.0084 |
| Admixed American134 / 35,410 | 0.0038 |
| African/African American62 / 24,966 | 0.0025 |
| South Asian2 / 30,616 | 6.5e-05 |
This variant is present in gnomAD v4.1 (AF= 0.0158629; MAF= 1.58629%, 25605/1614142 alleles, homozygotes = 263) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0193938; MAF= 1.93938%, 22885/1180016 alleles, homozygotes = 248); grpmax FAF= 0.0191827.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009721920486639148, 179/18412 alleles, homozygotes = 1).
The variant is a missense SNV, NM_001127701.1:c.1096G>A (NP_001121173.1:p.(Glu366Lys)); therefore the applicable generic computational path is REVEL only. REVEL is 0.686, meeting the supplied PP3 supporting threshold of >= 0.644 (ClinGen SVI calibration, Pejaver et al. 2022, PMID:36413997). SpliceAI max delta 0.00 and BayesDel 0.191219 are not used for PP3: SpliceAI is outside the missense path and no generic ACMG-strength calibration is established for BayesDel.
PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense SNV, so BP4 must be assessed through the generic REVEL path only. REVEL is 0.686, which is above the supplied BP4 supporting cutoff of <= 0.29 and therefore does not support a benign computational effect. The SpliceAI max delta of 0.00 is not applicable to BP4 for this missense variant, and BayesDel has no established generic ACMG-strength calibration.
BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001127701.1:c.1096G>A in SERPINA1 is a missense substitution predicted to produce NP_001121173.1:p.(Glu366Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for SERPINA1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.686. BayesDel score = 0.191219.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
The presence of mAb5E3 caused a detectable, but less pronounced, acceleration of A1AT polymerization.
Results, “mAb5E3 increases the rate of α1-antitrypsin polymerization”; Figure 5B
Therefore, we conclude that the aberrant conformation of α1-AT arises from the loss of the stabilizing interactions of Glu-342 in wild type α1-AT, rather than from the positive charge of Lys in the Z variant.
Results, “Role of Residue 342 in α1-AT Conformations”; Discussion, “Aberrant Conformation of Z α1-AT”
The SERPINA1 gene is located on the long arm of chromosome 14 (14q31–32·3); it spans 12·2 kb and is organised into four coding (2, 3, 4, and 5) and three non-coding (1a, 1b, and 1c) exons.
Genetics section; Table 1, Characteristics of selected SERPINA1 alleles
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.0158629; MAF= 1.58629%, 25605/1614142 alleles, homozygotes = 263) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0193938; MAF= 1.93938%, 22885/1180016 alleles, homozygotes = 248); grpmax FAF= 0.0191827.
This variant is present in gnomAD v2.1 (AF= 0.0112329; MAF= 1.12329%, 3176/282742 alleles, homozygotes = 26) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0183495; MAF= 1.83495%, 2369/129104 alleles, homozygotes = 23); grpmax FAF= 0.0177524.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009721920486639148, 179/18412 alleles, homozygotes = 1).
This variant has been reported in ClinVar as Pathogenic (45 clinical laboratories) and as risk factor (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 17967)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.686. BayesDel score = 0.191219.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99054006, n = 3 times).
This variant does not lie in a statistically significant hotspot.