ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.399G>A (p.Glu133=)
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
-
NM_001370658.1(BTD):c.399G>A (p.Glu133=)
Variation ID: 25009 Accession: VCV000025009.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.1 3: 15642057 (GRCh38) [ NCBI UCSC ] 3: 15683564 (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 Mar 8, 2017 Feb 28, 2024 Dec 26, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001370658.1:c.399G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Glu133= synonymous NM_000060.4:c.459G>A NP_000051.1:p.Glu153= synonymous NM_001281723.4:c.399G>A NP_001268652.2:p.Glu133= synonymous NM_001281724.3:c.399G>A NP_001268653.2:p.Glu133= synonymous NM_001281725.3:c.399G>A NP_001268654.1:p.Glu133= synonymous NM_001281726.3:c.399G>A NP_001268655.2:p.Glu133= synonymous NM_001323582.2:c.399G>A NP_001310511.1:p.Glu133= synonymous NM_001370752.1:c.399G>A NP_001357681.1:p.Glu133= synonymous NM_001370753.1:c.399G>A NP_001357682.1:p.Glu133= synonymous NM_001407364.1:c.399G>A NP_001394293.1:p.Glu133= synonymous NM_001407365.1:c.399G>A NP_001394294.1:p.Glu133= synonymous NM_001407366.1:c.399G>A NP_001394295.1:p.Glu133= synonymous NM_001407367.1:c.399G>A NP_001394296.1:p.Glu133= synonymous NM_001407368.1:c.399G>A NP_001394297.1:p.Glu133= synonymous NM_001407369.1:c.399G>A NP_001394298.1:p.Glu133= synonymous NM_001407370.1:c.399G>A NP_001394299.1:p.Glu133= synonymous NM_001407371.1:c.399G>A NP_001394300.1:p.Glu133= synonymous NM_001407372.1:c.399G>A NP_001394301.1:p.Glu133= synonymous NM_001407373.1:c.399G>A NP_001394302.1:p.Glu133= synonymous NM_001407374.1:c.399G>A NP_001394303.1:p.Glu133= synonymous NM_001407375.1:c.399G>A NP_001394304.1:p.Glu133= synonymous NM_001407376.1:c.399G>A NP_001394305.1:p.Glu133= synonymous NM_001407377.1:c.399G>A NP_001394306.1:p.Glu133= synonymous NM_001407378.1:c.399G>A NP_001394307.1:p.Glu133= synonymous NM_001407379.1:c.399G>A NP_001394308.1:p.Glu133= synonymous NM_001407380.1:c.399G>A NP_001394309.1:p.Glu133= synonymous NM_001407381.1:c.462G>A NP_001394310.1:p.Glu154= synonymous NM_001407382.1:c.399G>A NP_001394311.1:p.Glu133= synonymous NM_001407383.1:c.399G>A NP_001394312.1:p.Glu133= synonymous NM_001407384.1:c.399G>A NP_001394313.1:p.Glu133= synonymous NM_001407386.1:c.399G>A NP_001394315.1:p.Glu133= synonymous NM_001407388.1:c.399G>A NP_001394317.1:p.Glu133= synonymous NM_001407390.1:c.399G>A NP_001394319.1:p.Glu133= synonymous NM_001407392.1:c.399G>A NP_001394321.1:p.Glu133= synonymous NM_001407394.1:c.399G>A NP_001394323.1:p.Glu133= synonymous NM_001407395.1:c.399G>A NP_001394324.1:p.Glu133= synonymous NM_001407396.1:c.399G>A NP_001394325.1:p.Glu133= synonymous NM_001407397.1:c.399G>A NP_001394326.1:p.Glu133= synonymous NM_001407398.1:c.399G>A NP_001394327.1:p.Glu133= synonymous NM_001407399.1:c.399G>A NP_001394328.1:p.Glu133= synonymous NM_001407400.1:c.399G>A NP_001394329.1:p.Glu133= synonymous NM_001407401.1:c.399G>A NP_001394330.1:p.Glu133= synonymous NC_000003.12:g.15642057G>A NC_000003.11:g.15683564G>A NG_008019.2:g.45706G>A NG_008019.3:g.45707G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000003.12:15642056:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
---|---|---|---|---|---|---|
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. |
|||
BTD | - | - |
GRCh38 GRCh37 |
645 | 705 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 26, 2023 | RCV000021928.10 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 7, 2020 | RCV000425369.5 |
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
(Oct 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001758861.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek … (more)
In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10400129, 20556795, 11668630, 11865279, 9396567) (less)
|
|
Likely pathogenic
(Jul 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211442.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Dec 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000630333.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects codon 153 of the BTD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 153 of the BTD mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BTD protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs397514360, gnomAD 0.0009%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 10400129; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 25009). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Sep 23, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511171.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
Likely pathogenic
(Nov 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223036.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: BTD c.399G>A (p.Glu133Glu) alters the conserved, last nucleotide of exon 3 and therefore could affect mRNA splicing, leading to a significantly altered protein … (more)
Variant summary: BTD c.399G>A (p.Glu133Glu) alters the conserved, last nucleotide of exon 3 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions have yet to be confirmed by functional studies, although one study attempted to confirm a splicing impact but was unable to detect any aberrantly spliced transcripts or transcripts with the variant of interest in patients (e.g., Pomponio_1997). These findings suggest mRNA produced from the variant allele may be rapidly degraded. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.399G>A has been reported in the literature in several compound heterozygous individuals affected with Biotinidase Deficiency (e.g., Pomponio_1997, Norrgard_1999, Wolf_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that biotinyl-hydrolase activity was <10% of normal activity in serum from patients harboring a null variant in trans (e.g., Pomponio_1997, Norrgard_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10400129, 9396567, 11865279). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
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 |
---|---|---|---|---|
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Hearing loss is a common feature of symptomatic children with profound biotinidase deficiency. | Wolf B | The Journal of pediatrics | 2002 | PMID: 11865279 |
Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. | Norrgard KJ | Pediatric research | 1999 | PMID: 10400129 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. | Pomponio RJ | Pediatric research | 1997 | PMID: 9396567 |
Text-mined citations for rs397514360 ...
HelpRecord last updated Mar 05, 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.