ClinVar Genomic variation as it relates to human health
NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys)
Variation ID: 17974 Accession: VCV000017974.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.13 14: 94383051 (GRCh38) [ NCBI UCSC ] 14: 94849388 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 6, 2014 Jun 17, 2024 Mar 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000295.5:c.187C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000286.3:p.Arg63Cys missense NM_001002235.3:c.187C>T NP_001002235.1:p.Arg63Cys missense NM_001002236.3:c.187C>T NP_001002236.1:p.Arg63Cys missense NM_001127700.2:c.187C>T NP_001121172.1:p.Arg63Cys missense NM_001127701.2:c.187C>T NP_001121173.1:p.Arg63Cys missense NM_001127702.2:c.187C>T NP_001121174.1:p.Arg63Cys missense NM_001127703.2:c.187C>T NP_001121175.1:p.Arg63Cys missense NM_001127704.2:c.187C>T NP_001121176.1:p.Arg63Cys missense NM_001127705.2:c.187C>T NP_001121177.1:p.Arg63Cys missense NM_001127706.2:c.187C>T NP_001121178.1:p.Arg63Cys missense NM_001127707.2:c.187C>T NP_001121179.1:p.Arg63Cys missense NC_000014.9:g.94383051G>A NC_000014.8:g.94849388G>A NG_008290.1:g.12642C>T LRG_575:g.12642C>T LRG_575t1:c.187C>T LRG_575p1:p.Arg63Cys P01009:p.Arg63Cys - Protein change
- R63C
- Other names
- R39C
- SERPINA1, ARG39CYS ON M1V
- Canonical SPDI
- NC_000014.9:94383050:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on catalytic protein function Variation Ontology [VariO:0008]
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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.
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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Exome Aggregation Consortium (ExAC) 0.00097
The Genome Aggregation Database (gnomAD), exomes 0.00106
The Genome Aggregation Database (gnomAD) 0.00137
Trans-Omics for Precision Medicine (TOPMed) 0.00168
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 | ||
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HI score
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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. |
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SERPINA1 | - | - |
GRCh38 GRCh38 GRCh37 |
473 | 508 |
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. |
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Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2024 | RCV000148875.28 | |
PI I
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other (1) |
no assertion criteria provided
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Jul 15, 2016 | RCV000019575.5 |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2023 | RCV000431149.26 | |
SERPINA1-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV003390693.5 |
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. |
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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000389660.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The SERPINA1 c.187C>T (p.Arg63Cys) missense variant, more commonly known as p.Arg39Cys or the protease inhibitor (PI) type I variant (PI*I), is widely reported in the … (more)
The SERPINA1 c.187C>T (p.Arg63Cys) missense variant, more commonly known as p.Arg39Cys or the protease inhibitor (PI) type I variant (PI*I), is widely reported in the literature. Across a selection of the available literature, the p.Arg63Cys variant has been identified in a compound heterozygous state with a known pathogenic variant in at least 156 individuals with alpha-1 antitrypsin deficiency (Baur et al. 1987; Seri et al., 1992; Mahadeva et al. 1999; Ferrarotti et al., 2007; Zorzetto et al., 2008; Carroll et al., 2011; Donato et al., 2012; Suh-Lailam et al. 2014; Duk et al.2016; Silva et al. 2016). The p.Arg63Cys variant is reported at a frequency of 0.00298 in the European population of the 1000 Genomes Project. Mahadeva et al. (1999) performed an in vitro functional study and discovered the p.Arg63Cys variant protein is conformationally unstable and forms polymer chains, while the wild type SERPINA1 protein remains monomeric. The variant is thought to have a mild effect on the SERPINA1 protein and likely requires the contribution of a strongly pathogenic variant to cause disease. Based on the collective evidence, the p.Arg63Cys variant is classified as pathogenic for alpha-1 antitrypsin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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SERPINA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120316.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The SERPINA1 c.187C>T variant is predicted to result in the amino acid substitution p.Arg63Cys. This variant is also known as p.Arg39Cys and as the protease … (more)
The SERPINA1 c.187C>T variant is predicted to result in the amino acid substitution p.Arg63Cys. This variant is also known as p.Arg39Cys and as the protease inhibitor (PI) type I variant (PI*I). It has been reported as a mild Alpha-1 antitrypsin deficiency variant that requires the presence of a second strong deficiency variant to cause disease (Amendola et al. 2015. PubMed ID: 25637381; Baur and Bencze. 1987. PubMed ID: 3496639; Mahadeva et al. 1999. PubMed ID: 10194472; Silva et al. 2016. PubMed ID: 27296815; Giacopuzzi et al. 2018. PubMed ID: 29882371). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We classify this variant as likely pathogenic. (less)
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Pathogenic
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500625.19
First in ClinVar: Mar 14, 2021 Last updated: Jun 17, 2024 |
Comment:
SERPINA1: PS3, PS4, PP4:Moderate
Number of individuals with the variant: 4
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Likely pathogenic
(Aug 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000227088.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 16
Sex: mixed
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Alpha-1-antitrypsin deficiency
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251538.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
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Comment:
The SERPINA1 c.187C>T (p.R63C) variant (also known as the I allele) is a mildly deficient variant. Alpha-1 antitrypsin deficiency has been reported in individuals homozygous … (more)
The SERPINA1 c.187C>T (p.R63C) variant (also known as the I allele) is a mildly deficient variant. Alpha-1 antitrypsin deficiency has been reported in individuals homozygous for the SERPINA1 I allele, or if the I allele is present with a more severe SERPINA1 variant (i.e. SERPINA1 c.1096G>A, p.E366K, also known as the Z allele) (PMID: 2606478, 10194472; 22912357). (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782052.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000521230.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that the R63C variant impairs protein secretion by forming aberrant disulfide bonds (Ronzoni et al., 2016); In silico analysis supports that … (more)
Published functional studies demonstrate that the R63C variant impairs protein secretion by forming aberrant disulfide bonds (Ronzoni et al., 2016); 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: 24713750, 29882371, 26987331, 24055113, 25637381, 21228398, 23632999, 27296815, 30487145, 31447099, 31589614, 2606478, 26647313, 34426522, 31980526) (less)
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Pathogenic
(Feb 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844885.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: SERPINA1 c.187C>T (p.Arg63Cys) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of … (more)
Variant summary: SERPINA1 c.187C>T (p.Arg63Cys) results in a non-conservative amino acid change located in the Serpin domain (IPR023796) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251314 control chromosomes in the gnomAD database, including 1 homozygote. c.187C>T (also known as Arg39Cys and as I allele) has been reported in the literature in multiple individuals affected with Alpha-1-Antitrypsin Deficiency (e.g. Mahadeva_1999, Carroll_2011, Donato_2012, Gupta_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant exhibits decreased stability, and forms aberrant disulphide bonds leading to reduced secretion of a1-antitrypsin (Mahadeva_1999, Jung_2004, Ronzoni_2016). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as other. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jun 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019174.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000956623.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the SERPINA1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the SERPINA1 protein (p.Arg63Cys). This variant is present in population databases (rs28931570, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with alpha 1-antitrypsin deficiency when in combination with the p.Glu366Lys (Pi*Z) variant. Individuals with this missense change and the p.Glu288Val (Pi*S) variant have been reported with mild or no deficiency of alpha 1-antitrypsin (PMID: 2606478, 10194472, 21752289, 22912357, 24713750). This variant is also known as Arg39Cys and the I allele. ClinVar contains an entry for this variant (Variation ID: 17974). 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 affects SERPINA1 function (PMID: 10194472). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Mar 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005056682.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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other
(Jul 15, 2016)
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no assertion criteria provided
Method: literature only
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PI I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039872.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2016 |
Comment on evidence:
By gene amplification and direct DNA sequencing, Graham et al. (1989) identified this mutation, CGC to TGC, in a compound heterozygote. Homozygotes are at no … (more)
By gene amplification and direct DNA sequencing, Graham et al. (1989) identified this mutation, CGC to TGC, in a compound heterozygote. Homozygotes are at no risk of emphysema, but compound heterozygotes with Z or a null allele have a mildly increased risk (Crystal, 1989). In 1 individual and 3 independent families, Seri et al. (1992) confirmed that the I variant resulted from a CGC (arg)-to-TGC (cys) transition at codon 39 within exon 2. (less)
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Likely pathogenic
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Antitrypsin alpha 1 deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190619.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Pathogenic
(Dec 08, 2014)
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no assertion criteria provided
Method: curation
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Alpha-1-antitrypsin deficiency
Affected status: yes
Allele origin:
germline
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Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital
Accession: SCV000608304.1
First in ClinVar: Oct 26, 2017 Last updated: Oct 26, 2017
Comment:
Rare deficiency allele
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Comment:
Reduced enzyme activity
Clinical Features:
emphysema (present) , COPD (present)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on catalytic protein function
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Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital
Accession: SCV000608304.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Granularity of SERPINA1 alleles by DNA sequencing in CanCOLD. | Gupta N | The European respiratory journal | 2020 | PMID: 32482783 |
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 |
Frequency of Rare Alpha-1 Antitrypsin Variants in Polish Patients with Chronic Respiratory Disorders. | Duk K | Advances in experimental medicine and biology | 2016 | PMID: 26987331 |
Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants. | Ronzoni R | Human molecular genetics | 2016 | PMID: 26647313 |
Challenging identification of a novel PiISF and the rare PiMmaltonZ α1-antitrypsin deficiency variants in two patients. | Suh-Lailam BB | American journal of clinical pathology | 2014 | PMID: 24713750 |
Reference and interpretive ranges for α(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. | Donato LJ | American journal of clinical pathology | 2012 | PMID: 22912357 |
The prevalence of alpha-1 antitrypsin deficiency in Ireland. | Carroll TP | Respiratory research | 2011 | PMID: 21752289 |
SERPINA1 gene variants in individuals from the general population with reduced alpha1-antitrypsin concentrations. | Zorzetto M | Clinical chemistry | 2008 | PMID: 18515255 |
Laboratory diagnosis of alpha1-antitrypsin deficiency. | Ferrarotti I | Translational research : the journal of laboratory and clinical medicine | 2007 | PMID: 17964515 |
Retarded protein folding of deficient human alpha 1-antitrypsin D256V and L41P variants. | Jung CH | Protein science : a publication of the Protein Society | 2004 | PMID: 14767073 |
Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis. | Mahadeva R | The Journal of clinical investigation | 1999 | PMID: 10194472 |
Molecular characterization of the P and I variants of alpha 1-antitrypsin. | Seri M | International journal of clinical & laboratory research | 1992 | PMID: 1504305 |
The alpha 1-antitrypsin gene and its deficiency states. | Crystal RG | Trends in genetics : TIG | 1989 | PMID: 2696185 |
Molecular characterisation of three alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) nullcardiff (Asp256----Val); PiMmalton (Phe51----deletion) and PiI (Arg39----Cys). | Graham A | Human genetics | 1989 | PMID: 2606478 |
Study of familial alpha-1-proteinase inhibitor deficiency including a rare proteinase inhibitor phenotype (IZ). I. Alpha-1-phenotyping and clinical investigations. | Baur X | Respiration; international review of thoracic diseases | 1987 | PMID: 3496639 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1 | - | - | - | - |
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Text-mined citations for rs28931570 ...
HelpRecord last updated Jun 17, 2024
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.