ClinVar Genomic variation as it relates to human health
NM_000295.5(SERPINA1):c.1130dup (p.Leu377fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000295.5(SERPINA1):c.1130dup (p.Leu377fs)
Variation ID: 552891 Accession: VCV000552891.9
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 14q32.13 14: 94378575-94378576 (GRCh38) [ NCBI UCSC ] 14: 94844912-94844913 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 6, 2018 Feb 14, 2024 Sep 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000295.5:c.1130dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000286.3:p.Leu377fs frameshift NM_000295.4:c.1130dupT NM_001002235.3:c.1130dup NP_001002235.1:p.Leu377fs frameshift NM_001002236.3:c.1130dup NP_001002236.1:p.Leu377fs frameshift NM_001127700.2:c.1130dup NP_001121172.1:p.Leu377fs frameshift NM_001127701.2:c.1130dup NP_001121173.1:p.Leu377fs frameshift NM_001127702.2:c.1130dup NP_001121174.1:p.Leu377fs frameshift NM_001127703.2:c.1130dup NP_001121175.1:p.Leu377fs frameshift NM_001127704.2:c.1130dup NP_001121176.1:p.Leu377fs frameshift NM_001127705.2:c.1130dup NP_001121177.1:p.Leu377fs frameshift NM_001127706.2:c.1130dup NP_001121178.1:p.Leu377fs frameshift NM_001127707.2:c.1130dup NP_001121179.1:p.Leu377fs frameshift NC_000014.9:g.94378580dup NC_000014.8:g.94844917dup NG_008290.1:g.17117dup LRG_575:g.17117dup LRG_575t1:c.1130dup LRG_575p1:p.Leu377fs - Protein change
- L377fs
- Other names
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- Canonical SPDI
- NC_000014.9:94378575:AAAAA:AAAAAA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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 | ||
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HI score
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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. |
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SERPINA1 | - | - |
GRCh38 GRCh38 GRCh37 |
473 | 508 |
Conditions - Germline
Condition
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 12, 2023 | RCV000668239.9 |
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
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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. |
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Pathogenic
(Jul 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000792811.1
First in ClinVar: Aug 06, 2018 Last updated: Aug 06, 2018 |
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Pathogenic
(Sep 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203121.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Alpha-1-antitrypsin deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001591487.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SERPINA1 protein. Other variant(s) that disrupt this region … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the SERPINA1 protein. Other variant(s) that disrupt this region (p.Glu387Argfs*14) have been determined to be pathogenic (PMID: 9070606, 11334395, 22016686). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been reported to affect SERPINA1 protein function (PMID: 2539391). This variant has been observed in individual(s) with alpha-1-antitrypsin deficiency (PMID: 2539391, 21457231). It has also been observed to segregate with disease in related individuals. This variant is also known as Null Mattawa, L353fsX376, c.1126->T and Q0nancy in the literature. ClinVar contains an entry for this variant (Variation ID: 552891). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the SERPINA1 gene (p.Leu377Phefs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acids of the SERPINA1 protein. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Alpha-1-antitrypsin deficiency
(Codominant)
Affected status: yes
Allele origin:
unknown
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Child Health and Human Development Program, Research Institute of the McGill University Health Center
Accession: SCV001424552.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
The homozygous duplication of a single nucleotide [c.1130dup (p.Leu377fs)] in SERPINA1 was identified in a 65 year old female of Latin American origin being treated … (more)
The homozygous duplication of a single nucleotide [c.1130dup (p.Leu377fs)] in SERPINA1 was identified in a 65 year old female of Latin American origin being treated for emphysema. Her AAT level was 0.10 g/L. The AAT reference range at our institution is 0.99-2.59 g/L. (less)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Latin American
Comment on evidence:
Sixty five year old female of Latin American origin being treated for emphysema. Her AAT level was 0.10 g/L. The AAT reference range at our … (more)
Sixty five year old female of Latin American origin being treated for emphysema. Her AAT level was 0.10 g/L. The AAT reference range at our institution is 0.99-2.59 g/L. (less)
Testing laboratory: Fulgent
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. | Silva D | Respiratory medicine | 2016 | PMID: 27296815 |
[Alpha-1 antitrypsin deficiency caused by Null mutation]. | Perrin J | Revue des maladies respiratoires | 2016 | PMID: 26604020 |
Severe α-1 antitrypsin deficiency caused by Q0(Ourém) allele: clinical features, haplotype characterization and history. | Vaz Rodrigues L | Clinical genetics | 2012 | PMID: 21457231 |
Identification of compound heterozygous mutation in a Korean patient with alpha 1-antitrypsin deficiency. | Ko DH | The Korean journal of laboratory medicine | 2011 | PMID: 22016686 |
Compound heterozygosity for alpha-1-antitrypsin (S(iiyama) and QO(clayton)) in an Oriental patient. | Miyahara N | Internal medicine (Tokyo, Japan) | 2001 | PMID: 11334395 |
alpha1-antitrypsin gene mutation hot spot associated with the formation of a retained and degraded null variant [corrected; erratum to be published]. | Brantly M | American journal of respiratory cell and molecular biology | 1997 | PMID: 9070606 |
Secretion of alpha-1-proteinase inhibitor requires an almost full length molecule. | Brodbeck RM | The Journal of biological chemistry | 1992 | PMID: 1730596 |
Alpha 1-antitrypsin deficiency caused by the alpha 1-antitrypsin Nullmattawa gene. An insertion mutation rendering the alpha 1-antitrypsin gene incapable of producing alpha 1-antitrypsin. | Curiel D | The Journal of clinical investigation | 1989 | PMID: 2539391 |
Text-mined citations for rs763023697 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.