NM_000295.5(SERPINA1):c.206C>T (p.Ser69Phe) AND Alpha-1-antitrypsin deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 11, 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:: RCV000353319.6

Allele description [Variation Report for NM_000295.5(SERPINA1):c.206C>T (p.Ser69Phe)]

NM_000295.5(SERPINA1):c.206C>T (p.Ser69Phe)

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.206C>T (p.Ser69Phe)

HGVS:

NC_000014.9:g.94383032G>A
NG_008290.1:g.12661C>T
NM_000295.5:c.206C>TMANE SELECT
NM_001002235.3:c.206C>T
NM_001002236.3:c.206C>T
NM_001127700.2:c.206C>T
NM_001127701.2:c.206C>T
NM_001127702.2:c.206C>T
NM_001127703.2:c.206C>T
NM_001127704.2:c.206C>T
NM_001127705.2:c.206C>T
NM_001127706.2:c.206C>T
NM_001127707.2:c.206C>T
NP_000286.3:p.Ser69Phe
NP_001002235.1:p.Ser69Phe
NP_001002236.1:p.Ser69Phe
NP_001121172.1:p.Ser69Phe
NP_001121173.1:p.Ser69Phe
NP_001121174.1:p.Ser69Phe
NP_001121175.1:p.Ser69Phe
NP_001121176.1:p.Ser69Phe
NP_001121177.1:p.Ser69Phe
NP_001121178.1:p.Ser69Phe
NP_001121179.1:p.Ser69Phe
LRG_575t1:c.206C>T
LRG_575:g.12661C>T
LRG_575p1:p.Ser69Phe
NC_000014.8:g.94849369G>A
NM_000295.4:c.206C>T
P01009:p.Ser69Phe

Protein change:

S69F

Links:

UniProtKB: P01009#VAR_006983; dbSNP: rs199687431

Molecular consequence:

NM_000295.5:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.206C>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
SCV000389659	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV005770489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 11, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31661293, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000389659

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV005770489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 11, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.

Ortega VE, Li X, O'Neal WK, Lackey L, Ampleford E, Hawkins GA, Grayeski PJ, Laederach A, Barjaktarevic I, Barr RG, Cooper C, Couper D, Han MK, Kanner RE, Kleerup EC, Martinez FJ, Paine R 3rd, Peters SP, Pirozzi C, Rennard SI, Woodruff PG, Hoffman EA, et al.

Am J Respir Crit Care Med. 2020 Mar 1;201(5):540-554. doi: 10.1164/rccm.201904-0769OC.

PubMed [citation]

PMID:: 31661293
PMCID:: PMC7047460

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000389659.3

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV005770489.1

#	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 phenylalanine, which is neutral and non-polar, at codon 69 of the SERPINA1 protein (p.Ser69Phe). This variant is present in population databases (rs199687431, gnomAD 0.01%). This missense change has been observed in individual(s) with lung disease (PMID: 31661293). ClinVar contains an entry for this variant (Variation ID: 315030). Invitae Evidence 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 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. 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 12, 2026

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