ClinVar Genomic variation as it relates to human health
NM_001756.4(SERPINA6):c.1165G>A (p.Asp389Asn)
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.
Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001756.4(SERPINA6):c.1165G>A (p.Asp389Asn)
Variation ID: 16975 Accession: VCV000016975.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.13 14: 94304471 (GRCh38) [ NCBI UCSC ] 14: 94770808 (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 Apr 4, 2013 Feb 4, 2024 Feb 26, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001756.4:c.1165G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001747.3:p.Asp389Asn missense NC_000014.9:g.94304471C>T NC_000014.8:g.94770808C>T NG_011796.1:g.23881G>A P08185:p.Asp389Asn - Protein change
- D389N
- Other names
- D367N
- Canonical SPDI
- NC_000014.9:94304470:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00045
Exome Aggregation Consortium (ExAC) 0.00051
The Genome Aggregation Database (gnomAD), exomes 0.00062
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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SERPINA6 | - | - |
GRCh38 GRCh38 GRCh37 |
26 | 53 |
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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 26, 2022 | RCV000018496.36 |
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. |
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Uncertain significance
(Mar 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Corticosteroid-binding globulin deficiency
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001522660.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Jan 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Corticosteroid-binding globulin deficiency
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984212.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Likely pathogenic
(Feb 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Corticosteroid-binding globulin deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019176.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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CORTICOSTEROID-BINDING GLOBULIN DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038778.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 43-year-old woman with CBG deficiency (611489) who was referred for chronic asthenia and hypotension, Emptoz-Bonneton et al. (2000) found homozygosity for a 1254G-A … (more)
In a 43-year-old woman with CBG deficiency (611489) who was referred for chronic asthenia and hypotension, Emptoz-Bonneton et al. (2000) found homozygosity for a 1254G-A transition in exon 5 of the CBG gene, resulting in an asp367-to-asn (D367N) amino acid substitution. The variant was referred to as 'CBG Lyon.' The woman also had depression and very low serum cortisol concentration. In 2 Brazilian sisters with CBG deficiency, Brunner et al. (2003) identified a homozygous D367N substitution. CBG levels, cortisol levels, and cortisol-binding capacity were decreased. Heterozygous family members showed intermediate levels of these parameters. Neither of the homozygous sisters had hypotension, but 1 complained of fatigue. Buss et al. (2007) identified a heterozygous 1254G-T transversion in the SERPINA6 gene, resulting in the D367N substitution, in a 22-year-old Swiss male patient with severe muscle fatigue, usually after stressful events. Extensive biochemical and endocrine analysis showed decreased serum CBG and increased serum cortisol in response to ACTH or catecholamine administration. Investigation of other family members showed that the mutation occurred de novo on the paternal allele. Buss et al. (2007) proposed that SERPINA6 deficiency may act as an autosomal dominant disorder with incomplete penetrance, although a second pathogenic mutation could not be excluded. (less)
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Corticosteroid-binding globulin deficiency
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142444.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with … (more)
NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with autosomal recessive Corticosteroid-binding globulin deficiency, two homozygous c.1165G>A(PMID: 12780753; 20610591). Co-segregation evidence in a pedigree, two patients were affected and one sibling unaffected (PMID: 20610591). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PP1_Moderate; PM3; PP4; PP3. (less)
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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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Haploinsufficiency of the SERPINA6 gene is associated with severe muscle fatigue: A de novo mutation in corticosteroid-binding globulin deficiency. | Buss C | Journal of neural transmission (Vienna, Austria : 1996) | 2007 | PMID: 17245537 |
Hereditary corticosteroid-binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred. | Brunner E | Clinical endocrinology | 2003 | PMID: 12780753 |
Novel human corticosteroid-binding globulin variant with low cortisol-binding affinity. | Emptoz-Bonneton A | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10634411 |
Text-mined citations for rs28929488 ...
HelpRecord last updated Mar 17, 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.