VCV000017971.23 - ClinVar

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

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.

(12)

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.

Pathogenic/Likely pathogenic

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.194T>C (p.Leu65Pro)

Variation ID: 17971 Accession: VCV000017971.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.13 14: 94383044 (GRCh38) [ NCBI UCSC ] 14: 94849381 (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	Nov 14, 2015	Jul 23, 2024	Mar 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000295.5:c.194T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000286.3:p.Leu65Pro	missense
NM_001002235.3:c.194T>C	NP_001002235.1:p.Leu65Pro	missense
NM_001002236.3:c.194T>C	NP_001002236.1:p.Leu65Pro	missense
NM_001127700.2:c.194T>C	NP_001121172.1:p.Leu65Pro	missense
NM_001127701.2:c.194T>C	NP_001121173.1:p.Leu65Pro	missense
NM_001127702.2:c.194T>C	NP_001121174.1:p.Leu65Pro	missense
NM_001127703.2:c.194T>C	NP_001121175.1:p.Leu65Pro	missense
NM_001127704.2:c.194T>C	NP_001121176.1:p.Leu65Pro	missense
NM_001127705.2:c.194T>C	NP_001121177.1:p.Leu65Pro	missense
NM_001127706.2:c.194T>C	NP_001121178.1:p.Leu65Pro	missense
NM_001127707.2:c.194T>C	NP_001121179.1:p.Leu65Pro	missense
NC_000014.9:g.94383044A>G
NC_000014.8:g.94849381A>G
NG_008290.1:g.12649T>C
LRG_575:g.12649T>C
LRG_575t1:c.194T>C	LRG_575p1:p.Leu65Pro
	P01009:p.Leu65Pro

... more HGVS ... less HGVS

Protein change

L65P

Other names

L41P
SERPINA1, LEU41PRO ON M1V

Canonical SPDI

NC_000014.9:94383043:A:G

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

effect on catalytic protein function; Variation Ontology [ VariO:0008]

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA127686 UniProtKB: P01009#VAR_006982 OMIM: 107400.0016 dbSNP: rs28931569 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	483	518

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 M(PROCIDA)	other (1)	no assertion criteria provided	Jul 15, 2016	RCV000019571.11
Alpha-1-antitrypsin deficiency	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Mar 22, 2024	RCV000201848.26
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 17, 2017	RCV000729804.11
See cases	Likely pathogenic (1)	criteria provided, single submitter	Dec 5, 2021	RCV004584332.1

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.
Likely pathogenic (Dec 28, 2016)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788706.1 First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015	Publications: PubMed (5) PubMed: 3262617‚ 25391508‚ 18024524‚ 14767073‚ 9635295
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139507.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Jan 19, 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: SCV000893355.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Apr 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019173.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 04, 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: SCV000961591.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 3262617‚ 9635295‚ 14767073 Comment: 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). … (more) 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. (less)
Likely pathogenic (Mar 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004203115.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002054118.2 First in ClinVar: Jan 14, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PM1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Reduced circulating alpha-1-antitrypsin concentration (present) Age: 0-9 years Sex: male Tissue: blood
Likely pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086285.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 1975477‚ 9635295‚ 14767073 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as MPorcida allele or Leu41Pro in the literature, it has been reported in alpha-1-antitrypsin deficient patients, including those who were compound heterozygotes with null alleles (PMID: 1975477, 9635295; ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein has been showed to have retarded protein folding and were unable to form inhibitory complexes with target protease (PMID: 14767073). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000295.4:c.559A>T; p.(Lys187*)) in a recessive disease. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Oct 17, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000857495.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	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
other (Jul 15, 2016)	no assertion criteria provided Method: literature only	PI M(PROCIDA) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039868.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2016	Publications: PubMed (2) PubMed: 3262617‚ 2696185 Comment on evidence: Takahashi et al. (1988) showed that M(Procida) has a substitution of proline for leucine at position 41, resulting from a change of codon CTG to … (more) Takahashi et al. (1988) showed that M(Procida) has a substitution of proline for leucine at position 41, resulting from a change of codon CTG to CCG. The rare mutant protein shows somewhat reduced catalytic activity; its concentration is low in plasma, apparently because of instability and resulting intracellular degradation before secretion. Homozygotes have a high risk of emphysema (Crystal, 1989). (less)
Pathogenic (Dec 08, 2014)	no assertion criteria provided Method: curation	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital Accession: SCV000608305.1 First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015 Comment: Rare deficiency allele	Publications: PubMed (1) PubMed: 3262617 Comment: Reduced enzyme activity Clinical Features: emphysema (present) , COPD (present)
Pathogenic (May 01, 2014)	no assertion criteria provided Method: literature only	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000256622.1 First in ClinVar: Nov 14, 2015 Last updated: Nov 14, 2015 Comment: Disease association: lung	Publications: PubMed (1) PubMed: 14985567 Other databases http://www.ncbi.nlm.nih.gov/book… http://www.ncbi.nlm.nih.gov/books/NBK1519/
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Comment:

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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as MPorcida allele or Leu41Pro in the literature, it has been reported in alpha-1-antitrypsin deficient patients, including those who were compound heterozygotes with null alleles (PMID: 1975477, 9635295; ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein has been showed to have retarded protein folding and were unable to form inhibitory complexes with target protease (PMID: 14767073). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000295.4:c.559A>T; p.(Lys187*)) in a recessive disease. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on catalytic protein function (VariO:0008)			Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital Accession: SCV000608305.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alpha-1 Antitrypsin Deficiency.	Adam MP	-	2023	PMID: 20301692
Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy.	Balduyck M	Revue des maladies respiratoires	2014	PMID: 25391508
Inherited chronic obstructive pulmonary disease: new selective-sequencing workup for alpha1-antitrypsin deficiency identifies 2 previously unidentified null alleles.	Prins J	Clinical chemistry	2008	PMID: 18024524
Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk.	DeMeo DL	Thorax	2004	PMID: 14985567
Retarded protein folding of deficient human alpha 1-antitrypsin D256V and L41P variants.	Jung CH	Protein science : a publication of the Protein Society	2004	PMID: 14767073
Alpha 1-antitrypsin nonsense mutation associated with a retained truncated protein and reduced mRNA.	Lee J	Molecular genetics and metabolism	1998	PMID: 9635295
Alpha 1-antitrypsin Null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons.	Takahashi H	American journal of human genetics	1990	PMID: 1975477
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 alpha 1-antitrypsin "deficiency" allele Mprocida.	Takahashi H	The Journal of biological chemistry	1988	PMID: 3262617
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1	-	-	-	-

Text-mined citations for rs28931569 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28931569 ...