ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.641C>T (p.Thr214Ile)
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.641C>T (p.Thr214Ile)
Variation ID: 156003 Accession: VCV000156003.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644557 (GRCh38) [ NCBI UCSC ] 3: 15686064 (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 Feb 14, 2024 Sep 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370658.1:c.641C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Thr214Ile missense NM_000060.4:c.701C>T NP_000051.1:p.Thr234Ile missense NM_001281723.2:c.[707C>T] NM_001281723.4:c.641C>T NP_001268652.2:p.Thr214Ile missense NM_001281724.3:c.641C>T NP_001268653.2:p.Thr214Ile missense NM_001281725.3:c.641C>T NP_001268654.1:p.Thr214Ile missense NM_001323582.2:c.641C>T NP_001310511.1:p.Thr214Ile missense NM_001370752.1:c.641C>T NP_001357681.1:p.Thr214Ile missense NM_001370753.1:c.399+2500C>T intron variant NM_001407364.1:c.641C>T NP_001394293.1:p.Thr214Ile missense NM_001407365.1:c.641C>T NP_001394294.1:p.Thr214Ile missense NM_001407366.1:c.641C>T NP_001394295.1:p.Thr214Ile missense NM_001407367.1:c.641C>T NP_001394296.1:p.Thr214Ile missense NM_001407368.1:c.641C>T NP_001394297.1:p.Thr214Ile missense NM_001407369.1:c.641C>T NP_001394298.1:p.Thr214Ile missense NM_001407370.1:c.641C>T NP_001394299.1:p.Thr214Ile missense NM_001407371.1:c.641C>T NP_001394300.1:p.Thr214Ile missense NM_001407372.1:c.641C>T NP_001394301.1:p.Thr214Ile missense NM_001407373.1:c.641C>T NP_001394302.1:p.Thr214Ile missense NM_001407374.1:c.641C>T NP_001394303.1:p.Thr214Ile missense NM_001407375.1:c.641C>T NP_001394304.1:p.Thr214Ile missense NM_001407376.1:c.641C>T NP_001394305.1:p.Thr214Ile missense NM_001407377.1:c.641C>T NP_001394306.1:p.Thr214Ile missense NM_001407378.1:c.641C>T NP_001394307.1:p.Thr214Ile missense NM_001407379.1:c.641C>T NP_001394308.1:p.Thr214Ile missense NC_000003.12:g.15644557C>T NC_000003.11:g.15686064C>T NG_008019.2:g.48206C>T NG_008019.3:g.48207C>T - Protein change
- T214I
- Other names
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- Canonical SPDI
- NC_000003.12:15644556: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00003
1000 Genomes Project 30x 0.00031
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 |
647 | 724 |
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
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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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 9, 2023 | RCV000144060.21 |
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
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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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Likely pathogenic
(Oct 09, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915027.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The BTD c.701C>T (p.Thr234Ile) missense variant has been reported in at least three individuals, including in a homozygous state in one individual with profound biotinidase … (more)
The BTD c.701C>T (p.Thr234Ile) missense variant has been reported in at least three individuals, including in a homozygous state in one individual with profound biotinidase deficiency, and in a compound heterozygous state in two individuals, including one with profound and one with partial biotinidase deficiency (Li et al. 2014; Wolf et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00026 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Thr234Ile variant is classified as likely pathogenic for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(-)
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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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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073122.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
The missense variant p.T214I in BTD (NM_001281723.3) has been reported previously in homozygous and compound heterozygous state in affected individuals (Li H et al,Wolf B … (more)
The missense variant p.T214I in BTD (NM_001281723.3) has been reported previously in homozygous and compound heterozygous state in affected individuals (Li H et al,Wolf B et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. Functional data is not available for this variant. The p.T214I variant is observed in 8/30,616 (0.0261%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and isoleucine. The p.T214I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 214 of BTD is conserved in all mammalian species. The nucleotide c.641 in BTD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Recurrent spontaneous abortion (present)
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Pathogenic
(Dec 22, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819739.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: BTD c.641C>T (p.Thr214Ile), also known as c.701C>T (p.Thr234Ile), results in a non-conservative amino acid change in the encoded protein sequence. Five of five … (more)
Variant summary: BTD c.641C>T (p.Thr214Ile), also known as c.701C>T (p.Thr234Ile), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.641C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Biotinidase Deficiency (Li_2014, Wolf_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 22, 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: SCV004211441.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 09, 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: SCV000933006.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 234 of the BTD protein (p.Thr234Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 234 of the BTD protein (p.Thr234Ile). This variant is present in population databases (rs587783005, gnomAD 0.03%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 27657684). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 156003). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Nov 24, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002802574.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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: SCV000189133.1
First in ClinVar: Sep 22, 2014 Last updated: Sep 22, 2014 |
Number of individuals with the variant: 2
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Pathogenic
(Jun 15, 2017)
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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: SCV002081561.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. | Wolf B | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27657684 |
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 |
Text-mined citations for rs587783005 ...
HelpRecord last updated Apr 06, 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.