NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys) AND Alpha-1-antitrypsin deficiency

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000148875.28

Allele description [Variation Report for NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys)]

NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys)

Gene:

SERPINA1:serpin family A member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.13

Genomic location:

Preferred name:

NM_001127701.1(SERPINA1):c.187C>T (p.Arg63Cys)

Other names:

R39C; SERPINA1, ARG39CYS ON M1V

HGVS:

NC_000014.9:g.94383051G>A
NG_008290.1:g.12642C>T
NM_000295.5:c.187C>TMANE SELECT
NM_001002235.3:c.187C>T
NM_001002236.3:c.187C>T
NM_001127700.2:c.187C>T
NM_001127701.2:c.187C>T
NM_001127702.2:c.187C>T
NM_001127703.2:c.187C>T
NM_001127704.2:c.187C>T
NM_001127705.2:c.187C>T
NM_001127706.2:c.187C>T
NM_001127707.2:c.187C>T
NP_000286.3:p.Arg63Cys
NP_001002235.1:p.Arg63Cys
NP_001002236.1:p.Arg63Cys
NP_001121172.1:p.Arg63Cys
NP_001121173.1:p.Arg63Cys
NP_001121174.1:p.Arg63Cys
NP_001121175.1:p.Arg63Cys
NP_001121176.1:p.Arg63Cys
NP_001121177.1:p.Arg63Cys
NP_001121178.1:p.Arg63Cys
NP_001121179.1:p.Arg63Cys
LRG_575t1:c.187C>T
LRG_575:g.12642C>T
LRG_575p1:p.Arg63Cys
NC_000014.8:g.94849388G>A
NM_000295.4:c.187C>T
P01009:p.Arg63Cys

Protein change:

R63C; ARG39CYS

Links:

UniProtKB: P01009#VAR_006981; OMIM: 107400.0018; dbSNP: rs28931570

NCBI 1000 Genomes Browser:

rs28931570

Molecular consequence:

NM_000295.5:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on catalytic protein function [Variation Ontology: 0008]

Condition(s)

Name:: Alpha-1-antitrypsin deficiency (A1ATD)
Synonyms:: AAT deficiency; A1AT deficiency; Alpha1-Antitrypsin Deficiency
Identifiers:: MONDO: MONDO:0013282; MedGen: C0221757; Orphanet: 60; OMIM: 613490

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190619	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Likely pathogenic (Jun 1, 2014)	germline	research
SCV000389660	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 24713750, 3496639, 1504305, 10194472, 18515255, 22912357, 17964515, 27296815, 21752289, 26987331 Citation Link,
SCV000608304	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	no assertion criteria provided	Pathogenic (Dec 8, 2014)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV000956623	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 2606478, 21752289, 22912357, 24713750, 10194472, 28492532
SCV001251538	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (4) [See all records that cite these PMIDs] 2606478, 10194472, 22912357, 25741868
SCV002019174	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 24, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002782052	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 10, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003844885	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21752289, 22912357, 32482783, 14767073, 10194472, 26647313 Citation Link,
SCV005056682	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	no	1	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Study of familial alpha-1-proteinase inhibitor deficiency including a rare proteinase inhibitor phenotype (IZ). I. Alpha-1-phenotyping and clinical investigations.

Baur X, Bencze K.

Respiration. 1987;51(3):188-95.

PubMed [citation]

PMID:: 3496639

Molecular characterization of the P and I variants of alpha 1-antitrypsin.

Seri M, Magi B, Cellesi C, Olia PM, Renieri A, De Marchi M.

Int J Clin Lab Res. 1992;22(2):119-21.

PubMed [citation]

PMID:: 1504305

See all PubMed Citations (16)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190619.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000389660.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital, SCV000608304.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

Reduced enzyme activity

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000956623.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251538.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002019174.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002782052.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844885.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV005056682.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

Relating variation to medicine