ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.566G>A (p.Arg189His)
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_001370658.1(BTD):c.566G>A (p.Arg189His)
Variation ID: 92400 Accession: VCV000092400.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644482 (GRCh38) [ NCBI UCSC ] 3: 15685989 (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 Sep 22, 2014 Mar 16, 2024 Oct 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370658.1:c.566G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Arg189His missense NM_000060.4:c.626G>A NP_000051.1:p.Arg209His missense NM_001281723.4:c.566G>A NP_001268652.2:p.Arg189His missense NM_001281724.3:c.566G>A NP_001268653.2:p.Arg189His missense NM_001281725.3:c.566G>A NP_001268654.1:p.Arg189His missense NM_001323582.2:c.566G>A NP_001310511.1:p.Arg189His missense NM_001370752.1:c.566G>A NP_001357681.1:p.Arg189His missense NM_001370753.1:c.399+2425G>A intron variant NM_001407364.1:c.566G>A NP_001394293.1:p.Arg189His missense NM_001407365.1:c.566G>A NP_001394294.1:p.Arg189His missense NM_001407366.1:c.566G>A NP_001394295.1:p.Arg189His missense NM_001407367.1:c.566G>A NP_001394296.1:p.Arg189His missense NM_001407368.1:c.566G>A NP_001394297.1:p.Arg189His missense NM_001407369.1:c.566G>A NP_001394298.1:p.Arg189His missense NM_001407370.1:c.566G>A NP_001394299.1:p.Arg189His missense NM_001407371.1:c.566G>A NP_001394300.1:p.Arg189His missense NM_001407372.1:c.566G>A NP_001394301.1:p.Arg189His missense NM_001407373.1:c.566G>A NP_001394302.1:p.Arg189His missense NM_001407374.1:c.566G>A NP_001394303.1:p.Arg189His missense NM_001407375.1:c.566G>A NP_001394304.1:p.Arg189His missense NM_001407376.1:c.566G>A NP_001394305.1:p.Arg189His missense NM_001407377.1:c.566G>A NP_001394306.1:p.Arg189His missense NM_001407378.1:c.566G>A NP_001394307.1:p.Arg189His missense NM_001407379.1:c.566G>A NP_001394308.1:p.Arg189His missense NC_000003.12:g.15644482G>A NC_000003.11:g.15685989G>A NG_008019.2:g.48131G>A NG_008019.3:g.48132G>A - Protein change
- R189H
- Other names
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- Canonical SPDI
- NC_000003.12:15644481:G:A
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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), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00014
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
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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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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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2023 | RCV000144058.24 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000507456.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2023 | RCV003905037.1 |
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. |
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Pathogenic
(Aug 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000109914.8
First in ClinVar: Jan 17, 2014 Last updated: Sep 30, 2017 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Aug 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004211431.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000940981.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 92400). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg209 … (more)
ClinVar contains an entry for this variant (Variation ID: 92400). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg209 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 24797656, 25754625, 26361991, 26810761), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt BTD protein function. This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 25754625, 26361991). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs398123139, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the BTD protein (p.Arg209His). (less)
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Pathogenic
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602898.2
First in ClinVar: Mar 08, 2017 Last updated: Feb 20, 2024 |
Comment:
The BTD c.566G>A; p.Arg189His variant (rs398123139), also known as c.626G>A; p.Arg209His for NM_000060.2, has been reported in an individual with profound BTD deficiency, and found … (more)
The BTD c.566G>A; p.Arg189His variant (rs398123139), also known as c.626G>A; p.Arg209His for NM_000060.2, has been reported in an individual with profound BTD deficiency, and found in-trans with a pathogenic variant (Li 2014). Another missense variant at this residue, p.Arg189Cys, has been reported in an individual with partial BTD deficiency when found with a pathogenic variant (Procter 2016). The p.Arg189His variant is reported in ClinVar (Variation ID: 92400). It is observed in the general population with an overall allele frequency of 0.002% (7/282856 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.84). Based on the available information, the p.Arg189His variant is considered to be pathogenic. References: Li H et al. Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. Mol Genet Metab. 2014 Jul;112(3):242-6. PMID: 24797656. Procter M et al. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar;117(3):369-72. PMID: 26810761. (less)
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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BTD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004725007.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The BTD c.626G>A variant is predicted to result in the amino acid substitution p.Arg209His. This variant has been reported in the compound heterozygous state in … (more)
The BTD c.626G>A variant is predicted to result in the amino acid substitution p.Arg209His. This variant has been reported in the compound heterozygous state in individuals with biotinidase deficiency (Gannavarapu et al. 2015. PubMed ID: 26361991; Li et al. 2014. PubMed ID: 24797656; Karaca et al. 2015. PubMed ID: 25754625; Al-Jasmi et al. 2015. PubMed ID: 26589311). In vitro experimental studies suggest this variant impacts protein function (Li et al. 2014. PubMed ID: 24797656). An alternate nucleotide change affecting the same amino acid (p.Arg209Cys) has been reported in individuals with biotinidase deficiency (Procter et al. 2016. PubMed ID: 26810761; Kars et al. 2021. PubMed ID: 34426522). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-15685989-G-A). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446641.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Gait imbalance (present) , Hypotonia (present)
Sex: male
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Pathogenic
(Mar 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580763.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Jul 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600944.3
First in ClinVar: Sep 30, 2017 Last updated: Dec 31, 2022 |
Comment:
The variant has been found in at least one symptomatic patient. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in … (more)
The variant has been found in at least one symptomatic patient. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have phenotype known to be consistent with disease. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Biotinidase deficiency
Affected status: yes
Allele origin:
germline
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Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories
Accession: SCV000189131.1
First in ClinVar: Sep 22, 2014 Last updated: Sep 22, 2014 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001461218.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Forty-eight novel mutations causing biotinidase deficiency. | Procter M | Molecular genetics and metabolism | 2016 | PMID: 26810761 |
Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014). | Al-Jasmi FA | JIMD reports | 2016 | PMID: 26589311 |
Biotinidase deficiency: Spectrum of molecular, enzymatic and clinical information from newborn screening Ontario, Canada (2007-2014). | Gannavarapu S | Molecular genetics and metabolism | 2015 | PMID: 26361991 |
Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. | Karaca M | European journal of pediatrics | 2015 | PMID: 25754625 |
Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years. | Jay AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25144890 |
Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. | Li H | Molecular genetics and metabolism | 2014 | PMID: 24797656 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BTD | - | - | - | - |
Text-mined citations for rs398123139 ...
HelpRecord last updated Apr 15, 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.