This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the SERPINA1 protein (p.Pro393Leu). This variant is present in population databases (rs199422209, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive alpha-1-antitrypsin deficiency (AATD) (PMID: 2784123, 10234508, 18024524). This variant is also known as MHerleen and as Pro369Leu. ClinVar contains an entry for this variant (Variation ID: 17965). 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) performed at Invitae indicates that this missense variant is expected to disrupt SERPINA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234508, 18024524, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001127701.1(SERPINA1):c.1178C>T (p.Pro393Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(14)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001127701.1(SERPINA1):c.1178C>T (p.Pro393Leu)
Variation ID: 17965 Accession: VCV000017965.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q32.13 14: 94378528 (GRCh38) [ NCBI UCSC ] 14: 94844865 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 14, 2015 Oct 8, 2024 Mar 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000295.5:c.1178C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000286.3:p.Pro393Leu missense NM_001002235.3:c.1178C>T NP_001002235.1:p.Pro393Leu missense NM_001002236.3:c.1178C>T NP_001002236.1:p.Pro393Leu missense NM_001127700.2:c.1178C>T NP_001121172.1:p.Pro393Leu missense NM_001127701.2:c.1178C>T NP_001121173.1:p.Pro393Leu missense NM_001127702.2:c.1178C>T NP_001121174.1:p.Pro393Leu missense NM_001127703.2:c.1178C>T NP_001121175.1:p.Pro393Leu missense NM_001127704.2:c.1178C>T NP_001121176.1:p.Pro393Leu missense NM_001127705.2:c.1178C>T NP_001121177.1:p.Pro393Leu missense NM_001127706.2:c.1178C>T NP_001121178.1:p.Pro393Leu missense NM_001127707.2:c.1178C>T NP_001121179.1:p.Pro393Leu missense NC_000014.9:g.94378528G>A NC_000014.8:g.94844865G>A NG_008290.1:g.17165C>T LRG_575:g.17165C>T LRG_575t1:c.1178C>T LRG_575p1:p.Pro393Leu P01009:p.Pro393Leu - Protein change
- P393L
- Other names
-
P369L
SERPINA1, PRO369LEU ON M1A
Mheerlen
- Canonical SPDI
- NC_000014.9:94378527:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SERPINA1 | - | - |
GRCh38 GRCh38 GRCh37 |
487 | 523 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
|
PI M(HEERLEN)
|
other (1) |
no assertion criteria provided
|
Jul 20, 2016 | RCV000019565.3 |
|
SERPINA1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 15, 2024 | RCV003944831.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2017 | RCV002336088.2 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV000409001.17 | |
| Pathogenic (4) |
criteria provided, single submitter
|
Mar 14, 2017 | RCV000727230.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706787.2
First in ClinVar: Oct 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Jul 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Antitrypsin alpha 1 deficiency
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001449018.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely pathogenic
(Sep 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486942.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Nov 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591259.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the SERPINA1 protein (p.Pro393Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the SERPINA1 protein (p.Pro393Leu). This variant is present in population databases (rs199422209, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive alpha-1-antitrypsin deficiency (AATD) (PMID: 2784123, 10234508, 18024524). This variant is also known as MHerleen and as Pro369Leu. ClinVar contains an entry for this variant (Variation ID: 17965). 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) performed at Invitae indicates that this missense variant is expected to disrupt SERPINA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234508, 18024524, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810316.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jun 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002638503.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P393L pathogenic mutation (also known as c.1178C>T), located in coding exon 4 of the SERPINA1 gene, results from a C to T substitution at … (more)
The p.P393L pathogenic mutation (also known as c.1178C>T), located in coding exon 4 of the SERPINA1 gene, results from a C to T substitution at nucleotide position 1178. The proline at codon 393 is replaced by leucine, an amino acid with similar properties. This mutation comprises the deficiency allele PI*Mheerlen. The resulting mutant protein is not secreted but is retained in the endoplasmic reticulum (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). This mutation was identified in an individual in trans with a null allele with severe chronic obstructive pulmonary disease and extremely low serum alpha-1-antitrypsin levels (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203120.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
other
(Jul 20, 2016)
|
no assertion criteria provided
Method: literature only
|
PI M(HEERLEN)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039862.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 24, 2016 |
Comment on evidence:
Hofker et al. (1989) demonstrated the molecular defect in the PI gene of a patient with a serum level of only 5 mg/100 ml and … (more)
Hofker et al. (1989) demonstrated the molecular defect in the PI gene of a patient with a serum level of only 5 mg/100 ml and a PI M-like phenotype, designated PI M(Heerlen). They demonstrated a substitution of leucine for proline at codon 369, which resulted from a C-to-T mutation in exon 5. Otherwise the nucleotide sequence of the exons, intron/exon junctions, and a part of the promoter region was similar to that of a PI M1(ala213) gene. Kalsheker et al. (1992) described a family with Pi M(Heerlen) and commented on the difficulties of diagnosis of rare PI (null) or Q0 variants. (less)
|
|
|
Pathogenic
(May 01, 2014)
|
no assertion criteria provided
Method: literature only
|
Alpha-1-antitrypsin deficiency
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000256621.1
First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015
Comment:
Disease association: lung
|
|
|
|
Pathogenic
(Dec 08, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Alpha-1-antitrypsin deficiency
Affected status: yes
Allele origin:
germline
|
Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital
Accession: SCV000608300.1
First in ClinVar: Oct 26, 2017 Last updated: Oct 26, 2017 |
Clinical Features:
emphysema (present) , COPD (present) , liver disease (present)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809663.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739769.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968697.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Jul 15, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SERPINA1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004766713.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SERPINA1 c.1178C>T variant is predicted to result in the amino acid substitution p.Pro393Leu. This variant has been reported in multiple individuals with alpha-1-antitrypsin deficiency … (more)
The SERPINA1 c.1178C>T variant is predicted to result in the amino acid substitution p.Pro393Leu. This variant has been reported in multiple individuals with alpha-1-antitrypsin deficiency and has been referred to as the PI MHeerlen allele (Hofker et al. 1989. PubMed ID: 2784123; Poller et al. 1999. PubMed ID: 10234508; Giacopuzzi et al. 2018. PubMed ID: 29882371). Functional studies found this variant results in retention of the protein in the endoplasmic reticulum (Poller et al. 1999. PubMed ID: 10234508). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The p.P393L pathogenic mutation (also known as c.1178C>T), located in coding exon 4 of the SERPINA1 gene, results from a C to T substitution at nucleotide position 1178. The proline at codon 393 is replaced by leucine, an amino acid with similar properties. This mutation comprises the deficiency allele PI*Mheerlen. The resulting mutant protein is not secreted but is retained in the endoplasmic reticulum (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). This mutation was identified in an individual in trans with a null allele with severe chronic obstructive pulmonary disease and extremely low serum alpha-1-antitrypsin levels (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The SERPINA1 c.1178C>T variant is predicted to result in the amino acid substitution p.Pro393Leu. This variant has been reported in multiple individuals with alpha-1-antitrypsin deficiency and has been referred to as the PI MHeerlen allele (Hofker et al. 1989. PubMed ID: 2784123; Poller et al. 1999. PubMed ID: 10234508; Giacopuzzi et al. 2018. PubMed ID: 29882371). Functional studies found this variant results in retention of the protein in the endoplasmic reticulum (Poller et al. 1999. PubMed ID: 10234508). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the SERPINA1 protein (p.Pro393Leu). This variant is present in population databases (rs199422209, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive alpha-1-antitrypsin deficiency (AATD) (PMID: 2784123, 10234508, 18024524). This variant is also known as MHerleen and as Pro369Leu. ClinVar contains an entry for this variant (Variation ID: 17965). 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) performed at Invitae indicates that this missense variant is expected to disrupt SERPINA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 10234508). This variant disrupts the p.Pro393 amino acid residue in SERPINA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234508, 18024524, 27296815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.P393L pathogenic mutation (also known as c.1178C>T), located in coding exon 4 of the SERPINA1 gene, results from a C to T substitution at nucleotide position 1178. The proline at codon 393 is replaced by leucine, an amino acid with similar properties. This mutation comprises the deficiency allele PI*Mheerlen. The resulting mutant protein is not secreted but is retained in the endoplasmic reticulum (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). This mutation was identified in an individual in trans with a null allele with severe chronic obstructive pulmonary disease and extremely low serum alpha-1-antitrypsin levels (Poller W et al. Eur. J. Hum. Genet., 1999 Apr;7:321-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The SERPINA1 c.1178C>T variant is predicted to result in the amino acid substitution p.Pro393Leu. This variant has been reported in multiple individuals with alpha-1-antitrypsin deficiency and has been referred to as the PI MHeerlen allele (Hofker et al. 1989. PubMed ID: 2784123; Poller et al. 1999. PubMed ID: 10234508; Giacopuzzi et al. 2018. PubMed ID: 29882371). Functional studies found this variant results in retention of the protein in the endoplasmic reticulum (Poller et al. 1999. PubMed ID: 10234508). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Alpha-1 Antitrypsin Deficiency. | Adam MP | - | 2023 | PMID: 20301692 |
| Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. | Silva D | Respiratory medicine | 2016 | PMID: 27296815 |
| SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis. | Graham RP | The Journal of molecular diagnostics : JMD | 2015 | PMID: 26321041 |
| Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy. | Balduyck M | Revue des maladies respiratoires | 2014 | PMID: 25391508 |
| Inherited chronic obstructive pulmonary disease: new selective-sequencing workup for alpha1-antitrypsin deficiency identifies 2 previously unidentified null alleles. | Prins J | Clinical chemistry | 2008 | PMID: 18024524 |
| Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. | DeMeo DL | Thorax | 2004 | PMID: 14985567 |
| Molecular characterisation of the defective alpha 1-antitrypsin alleles PI Mwurzburg (Pro369Ser), Mheerlen (Pro369Leu), and Q0lisbon (Thr68Ile). | Poller W | European journal of human genetics : EJHG | 1999 | PMID: 10234508 |
| What is Pi (proteinase inhibitor) null or PiQO?: a problem highlighted by the alpha 1 antitrypsin Mheerlen mutation. | Kalsheker N | Journal of medical genetics | 1992 | PMID: 1552539 |
| A Pro----Leu substitution in codon 369 of the alpha-1-antitrypsin deficiency variant PI MHeerlen. | Hofker MH | Human genetics | 1989 | PMID: 2784123 |
| Deoxyribonucleic acid (DNA) polymorphism of the alpha 1-antitrypsin gene in chronic lung disease. | Kalsheker NA | British medical journal (Clinical research ed.) | 1987 | PMID: 3038256 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs199422209 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.