VCV000017957.27 - ClinVar

NM_001127701.1(SERPINA1):c.374G>A (p.Arg125His)

Germline

Classification

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)

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.

Benign

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.374G>A (p.Arg125His)

Variation ID: 17957 Accession: VCV000017957.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.13 14: 94382864 (GRCh38) [ NCBI UCSC ] 14: 94849201 (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	Jul 19, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000295.5:c.374G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000286.3:p.Arg125His	missense
NM_001002235.3:c.374G>A	NP_001002235.1:p.Arg125His	missense
NM_001002236.3:c.374G>A	NP_001002236.1:p.Arg125His	missense
NM_001127700.2:c.374G>A	NP_001121172.1:p.Arg125His	missense
NM_001127701.2:c.374G>A	NP_001121173.1:p.Arg125His	missense
NM_001127702.2:c.374G>A	NP_001121174.1:p.Arg125His	missense
NM_001127703.2:c.374G>A	NP_001121175.1:p.Arg125His	missense
NM_001127704.2:c.374G>A	NP_001121176.1:p.Arg125His	missense
NM_001127705.2:c.374G>A	NP_001121177.1:p.Arg125His	missense
NM_001127706.2:c.374G>A	NP_001121178.1:p.Arg125His	missense
NM_001127707.2:c.374G>A	NP_001121179.1:p.Arg125His	missense
NC_000014.9:g.94382864C>T
NC_000014.8:g.94849201C>T
NG_008290.1:g.12829G>A
LRG_575:g.12829G>A
LRG_575t1:c.374G>A	LRG_575p1:p.Arg125His
	P01009:p.Arg125His

... more HGVS ... less HGVS

Protein change

R125H

Other names

R101H
PI M4
SERPINA1, ARG101HIS ON M3
SERPINA1, ARG101HIS ON M1V

Canonical SPDI

NC_000014.9:94382863:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.16054 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.11726

The Genome Aggregation Database (gnomAD) 0.11804

1000 Genomes Project 30x 0.15162

The Genome Aggregation Database (gnomAD), exomes 0.15998

1000 Genomes Project 0.16054

Exome Aggregation Consortium (ExAC) 0.16313

Links

ClinGen: CA127621 UniProtKB: P01009#VAR_006991 OMIM: 107400.0003 OMIM: 107400.0005 dbSNP: rs709932 VarSome

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
Gene	OMIM	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	484	519

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 M2	other (1)	no assertion criteria provided	Jul 15, 2016	RCV000019557.4
PI M4	other (1)	no assertion criteria provided	Jul 15, 2016	RCV000019559.3
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Aug 25, 2016	RCV000155576.15
Alpha-1-antitrypsin deficiency	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000310904.18
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jul 9, 2018	RCV001636605.4
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Aug 2, 2017	RCV002345248.2

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.
Benign (Aug 25, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000345157.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 2901226 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1 Number of individuals with the variant: 1 Sex: mixed
Benign (Jul 09, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001849744.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021	Comment: This variant is associated with the following publications: (PMID: 22426792, 27153395, 2339709, 20981092, 14551891, 2901226)
Benign (Aug 02, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002622158.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303520.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 06, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205278.5 First in ClinVar: Jan 31, 2015 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 14551891 Comment: p.Arg125His in exon 4 of SERPINA1: This variant is not expected to have clinical significance because it has been identified in 27% (4488/16512) of South … (more) p.Arg125His in exon 4 of SERPINA1: This variant is not expected to have clinical significance because it has been identified in 27% (4488/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs709932). (less) Number of individuals with the variant: 24
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000389655.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808178.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001729056.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005293377.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
other (Jul 15, 2016)	no assertion criteria provided Method: literature only	PI M2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039854.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2016	Publications: PubMed (1) PubMed: 2901226 Cox, D. W. Alpha-1-antitrypsin (more...) Cox, D. W. Alpha-1-antitrypsin deficiency. In: Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (eds.) The Metabolic Basis of Inherited Disease. (6th ed.) New York: McGraw-Hill (pub.) 1989. Comment on evidence: M2, which has a frequency of 0.10-0.11 in US Caucasians (Cox, 1989), was studied by Nukiwa et al. (1988), who found that its coding exons … (more) M2, which has a frequency of 0.10-0.11 in US Caucasians (Cox, 1989), was studied by Nukiwa et al. (1988), who found that its coding exons are identical to those of the more frequent form of M1 (val213) except for 2 bases: a change in codon 101 from CGT to CAT, leading to an amino acid change of arginine to histidine; and a change in codon 376 from GAA to GAC, resulting in an amino acid change from glutamic acid to aspartic acid. Since 2 mutations separate these 2 common alleles, Nukiwa et al. (1988) suggested that another AAT variant (presumably M3) was an intermediate in their evolution. (less)
other (Jul 15, 2016)	no assertion criteria provided Method: literature only	PI M4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039856.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2016	Comment on evidence: M4, an uncommon normal allele, is likely derived by single substitution from M1V; however, it has the same mutation that changed M2 to M3, and … (more) M4, an uncommon normal allele, is likely derived by single substitution from M1V; however, it has the same mutation that changed M2 to M3, and thus it is possible that M4 derived from M3 (or vice versa). (less)
Benign (Dec 08, 2014)	no assertion criteria provided Method: curation	Alpha-1-antitrypsin deficiency Affected status: no Allele origin: germline	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital Accession: SCV000608314.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 Comment: Common normal allele	Publications: PubMed (1) PubMed: 2696185
Benign (-)	no assertion criteria provided Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733414.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001974857.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

p.Arg125His in exon 4 of SERPINA1: This variant is not expected to have clinical significance because it has been identified in 27% (4488/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs709932).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Are polymorphic markers within the alpha-1-antitrypsin gene associated with risk of human immunodeficiency virus disease?	Hayes VM	The Journal of infectious diseases	2003	PMID: 14551891
The alpha 1-antitrypsin gene and its deficiency states.	Crystal RG	Trends in genetics : TIG	1989	PMID: 2696185
Characterization of the gene and protein of the common alpha 1-antitrypsin normal M2 allele.	Nukiwa T	American journal of human genetics	1988	PMID: 2901226
Cox, D. W. Alpha-1-antitrypsin deficiency. In: Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D. (eds.) The Metabolic Basis of Inherited Disease. (6th ed.) New York: McGraw-Hill (pub.) 1989.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1	-	-	-	-

Text-mined citations for rs709932 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001127701.1(SERPINA1):c.374G>A (p.Arg125His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs709932 ...