NM_001127701.1(SERPINA1):c.194T>C (p.Leu65Pro) AND Alpha-1-antitrypsin deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 4, 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:: RCV000201848.22

Allele description

NM_001127701.1(SERPINA1):c.194T>C (p.Leu65Pro)

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.194T>C (p.Leu65Pro)

Other names:

L41P; SERPINA1, LEU41PRO ON M1V

HGVS:

NC_000014.9:g.94383044A>G
NG_008290.1:g.12649T>C
NM_000295.5:c.194T>CMANE SELECT
NM_001002235.3:c.194T>C
NM_001002236.3:c.194T>C
NM_001127700.2:c.194T>C
NM_001127701.2:c.194T>C
NM_001127702.2:c.194T>C
NM_001127703.2:c.194T>C
NM_001127704.2:c.194T>C
NM_001127705.2:c.194T>C
NM_001127706.2:c.194T>C
NM_001127707.2:c.194T>C
NP_000286.3:p.Leu65Pro
NP_001002235.1:p.Leu65Pro
NP_001002236.1:p.Leu65Pro
NP_001121172.1:p.Leu65Pro
NP_001121173.1:p.Leu65Pro
NP_001121174.1:p.Leu65Pro
NP_001121175.1:p.Leu65Pro
NP_001121176.1:p.Leu65Pro
NP_001121177.1:p.Leu65Pro
NP_001121178.1:p.Leu65Pro
NP_001121179.1:p.Leu65Pro
LRG_575t1:c.194T>C
LRG_575:g.12649T>C
LRG_575p1:p.Leu65Pro
NC_000014.8:g.94849381A>G
NM_000295.4:c.194T>C
P01009:p.Leu65Pro

Protein change:

L65P; LEU41PRO

Links:

UniProtKB: P01009#VAR_006982; OMIM: 107400.0016; dbSNP: rs28931569

NCBI 1000 Genomes Browser:

rs28931569

Molecular consequence:

NM_000295.5:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001002235.3:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001002236.3:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127700.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127701.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127702.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127703.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127704.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127705.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127706.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127707.2:c.194T>C - 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
SCV000256622	GeneReviews	no assertion criteria provided	Pathogenic (May 1, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000608305	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]
SCV000788706	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Dec 28, 2016)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 3262617, 25391508, 18024524, 14767073, 9635295 Citation Link,
SCV000893355	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 19, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000961591	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 3262617, 9635295, 14767073, 28492532
SCV001139507	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002019173	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004203115	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

Disease association: lung: SCV000256622

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	literature only, curation
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

Citations

PubMed

Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk.

DeMeo DL, Silverman EK.

Thorax. 2004 Mar;59(3):259-64. Review.

PubMed [citation]

PMID:: 14985567
PMCID:: PMC1746953

Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy.

Balduyck M, Odou MF, Zerimech F, Porchet N, Lafitte JJ, Maitre B.

Rev Mal Respir. 2014 Oct;31(8):729-45. doi: 10.1016/j.rmr.2014.06.001. Epub 2014 Jul 3. Review.

PubMed [citation]

PMID:: 25391508

See all PubMed Citations (8)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From GeneReviews, SCV000256622.1

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

#	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 Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital, SCV000608305.1

#	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 Counsyl, SCV000788706.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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, SCV000893355.2

#	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, SCV000961591.6

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 65 of the SERPINA1 protein (p.Leu65Pro). This variant is present in population databases (rs28931569, gnomAD 0.009%). This missense change has been observed in individual(s) with alpha 1-antitrypsin deficiency (PMID: 3262617, 9635295). 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 M procida and p.Leu41Pro. ClinVar contains an entry for this variant (Variation ID: 17971). 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 not expected to disrupt SERPINA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 14767073). For these reasons, this variant has been 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 Mendelics, SCV001139507.1

#	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 Revvity Omics, Revvity, SCV002019173.3

#	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 Baylor Genetics, SCV004203115.1

#	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: May 1, 2024

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