NM_001127701.1(SERPINA1):c.17C>T (p.Ser6Leu) AND Alpha-1-antitrypsin deficiency

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 14, 2023
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:: RCV000148880.12

Allele description [Variation Report for NM_001127701.1(SERPINA1):c.17C>T (p.Ser6Leu)]

NM_001127701.1(SERPINA1):c.17C>T (p.Ser6Leu)

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.17C>T (p.Ser6Leu)

HGVS:

NC_000014.9:g.94383221G>A
NG_008290.1:g.12472C>T
NM_000295.5:c.17C>TMANE SELECT
NM_001002235.3:c.17C>T
NM_001002236.3:c.17C>T
NM_001127700.2:c.17C>T
NM_001127701.2:c.17C>T
NM_001127702.2:c.17C>T
NM_001127703.2:c.17C>T
NM_001127704.2:c.17C>T
NM_001127705.2:c.17C>T
NM_001127706.2:c.17C>T
NM_001127707.2:c.17C>T
NP_000286.3:p.Ser6Leu
NP_001002235.1:p.Ser6Leu
NP_001002236.1:p.Ser6Leu
NP_001121172.1:p.Ser6Leu
NP_001121172.1:p.Ser6Leu
NP_001121173.1:p.Ser6Leu
NP_001121174.1:p.Ser6Leu
NP_001121175.1:p.Ser6Leu
NP_001121176.1:p.Ser6Leu
NP_001121177.1:p.Ser6Leu
NP_001121178.1:p.Ser6Leu
NP_001121179.1:p.Ser6Leu
LRG_575t1:c.17C>T
LRG_575:g.12472C>T
LRG_575p1:p.Ser6Leu
NC_000014.8:g.94849558G>A
NM_000295.4:c.17C>T
NM_001127700.1:c.17C>T

Protein change:

S6L

Links:

OMIM: 107400.0032; dbSNP: rs140814100

NCBI 1000 Genomes Browser:

rs140814100

Molecular consequence:

NM_000295.5:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.17C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.17C>T - 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
SCV000190624	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000608303	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	no assertion criteria provided	Pathogenic (Dec 8, 2014)	germline	clinical testing
SCV000796829	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jan 8, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002781991	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 16, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004678177	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 2227940, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Molecular characterisation of two alpha-1-antitrypsin deficiency variants: proteinase inhibitor (Pi) Null(Newport) (Gly115----Ser) and (Pi) Z Wrexham (Ser-19----Leu).

Graham A, Kalsheker NA, Bamforth FJ, Newton CR, Markham AF.

Hum Genet. 1990 Oct;85(5):537-40.

PubMed [citation]

PMID:: 2227940

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190624.1

#	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 Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital, SCV000608303.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000796829.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002781991.1

#	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 Invitae, SCV004678177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 6 of the SERPINA1 protein (p.Ser6Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with SERPINA1-related conditions (PMID: 2227940). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Ser(-19)Leu. ClinVar contains an entry for this variant (Variation ID: 17970). 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 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Apr 20, 2024

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