NM_000295.5(SERPINA1):c.514G>A (p.Gly172Arg) AND Alpha-1-antitrypsin deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jan 17, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000512621.27

Allele description [Variation Report for NM_000295.5(SERPINA1):c.514G>A (p.Gly172Arg)]

NM_000295.5(SERPINA1):c.514G>A (p.Gly172Arg)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.13

Genomic location:

Preferred name:

NM_000295.5(SERPINA1):c.514G>A (p.Gly172Arg)

Other names:

G148R

HGVS:

NC_000014.9:g.94382724C>T
NG_008290.1:g.12969G>A
NM_000295.5:c.514G>AMANE SELECT
NM_001002235.3:c.514G>A
NM_001002236.3:c.514G>A
NM_001127700.2:c.514G>A
NM_001127701.2:c.514G>A
NM_001127702.2:c.514G>A
NM_001127703.2:c.514G>A
NM_001127704.2:c.514G>A
NM_001127705.2:c.514G>A
NM_001127706.2:c.514G>A
NM_001127707.2:c.514G>A
NP_000286.3:p.Gly172Arg
NP_001002235.1:p.Gly172Arg
NP_001002236.1:p.Gly172Arg
NP_001121172.1:p.Gly172Arg
NP_001121173.1:p.Gly172Arg
NP_001121174.1:p.Gly172Arg
NP_001121175.1:p.Gly172Arg
NP_001121176.1:p.Gly172Arg
NP_001121177.1:p.Gly172Arg
NP_001121178.1:p.Gly172Arg
NP_001121179.1:p.Gly172Arg
LRG_575t1:c.514G>A
LRG_575:g.12969G>A
LRG_575p1:p.Gly172Arg
NC_000014.8:g.94849061C>T
NM_000295.4:c.514G>A

Protein change:

G172R

Links:

OMIM: 107400.0017; dbSNP: rs112030253

NCBI 1000 Genomes Browser:

rs112030253

Molecular consequence:

NM_000295.5:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.514G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000608318	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	no assertion criteria provided	Uncertain significance (Dec 8, 2014)	germline	curation
SCV000796768	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 28, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 2309708, 7977369, 11524735 Citation Link,
SCV001001964	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001139506	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001274083	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular analysis of the gene of the alpha 1-antitrypsin deficiency variant, Mnichinan.

Matsunaga E, Shiokawa S, Nakamura H, Maruyama T, Tsuda K, Fukumaki Y.

Am J Hum Genet. 1990 Mar;46(3):602-12.

PubMed [citation]

PMID:: 2309708
PMCID:: PMC1683626

Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele.

Faber JP, Poller W, Weidinger S, Kirchgesser M, Schwaab R, Bidlingmaier F, Olek K.

Am J Hum Genet. 1994 Dec;55(6):1113-21.

PubMed [citation]

PMID:: 7977369
PMCID:: PMC1918455

See all PubMed Citations (4)

Details of each submission

From Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital, SCV000608318.1

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

#	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 Counsyl, SCV000796768.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001001964.7

#	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 Mendelics, SCV001139506.1

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

#	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 Illumina Laboratory Services, Illumina, SCV001274083.1

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

Description

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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

Last Updated: Oct 13, 2024

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