Variant summary: BTD c.704T>C (p.Ile235Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251440 control chromosomes (gnomAD). c.704T>C has been reported in the literature in at least three compound heterozygous individuals affected with Biotinidase Deficiency (Ohlsson_2010, Jay_2015), who carried a pathogenic variant in trans. In one of the reported patients the biotinidase activity in plasma was immeasurable, suggesting this variant results in profound Biotinidase deficiency (Ohlsson_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic, or as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.704T>C (p.Ile235Thr)
Germline
Classification
Help
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.
(4)
Help
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.
Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(1)
Likely pathogenic(3); Uncertain significance(1)
4
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370658.1(BTD):c.704T>C (p.Ile235Thr)
Variation ID: 25040 Accession: VCV000025040.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644620 (GRCh38) [ NCBI UCSC ] 3: 15686127 (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 Jun 17, 2024 Mar 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.704T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Ile235Thr missense NM_000060.4:c.764T>C NP_000051.1:p.Ile255Thr missense NM_001281723.4:c.704T>C NP_001268652.2:p.Ile235Thr missense NM_001281724.3:c.704T>C NP_001268653.2:p.Ile235Thr missense NM_001281725.3:c.704T>C NP_001268654.1:p.Ile235Thr missense NM_001323582.2:c.704T>C NP_001310511.1:p.Ile235Thr missense NM_001370752.1:c.704T>C NP_001357681.1:p.Ile235Thr missense NM_001370753.1:c.399+2563T>C intron variant NM_001407364.1:c.704T>C NP_001394293.1:p.Ile235Thr missense NM_001407365.1:c.704T>C NP_001394294.1:p.Ile235Thr missense NM_001407366.1:c.704T>C NP_001394295.1:p.Ile235Thr missense NM_001407367.1:c.704T>C NP_001394296.1:p.Ile235Thr missense NM_001407368.1:c.704T>C NP_001394297.1:p.Ile235Thr missense NM_001407369.1:c.704T>C NP_001394298.1:p.Ile235Thr missense NM_001407370.1:c.704T>C NP_001394299.1:p.Ile235Thr missense NM_001407371.1:c.704T>C NP_001394300.1:p.Ile235Thr missense NM_001407372.1:c.704T>C NP_001394301.1:p.Ile235Thr missense NM_001407373.1:c.704T>C NP_001394302.1:p.Ile235Thr missense NM_001407374.1:c.704T>C NP_001394303.1:p.Ile235Thr missense NM_001407375.1:c.704T>C NP_001394304.1:p.Ile235Thr missense NM_001407376.1:c.704T>C NP_001394305.1:p.Ile235Thr missense NM_001407377.1:c.704T>C NP_001394306.1:p.Ile235Thr missense NM_001407378.1:c.704T>C NP_001394307.1:p.Ile235Thr missense NM_001407379.1:c.704T>C NP_001394308.1:p.Ile235Thr missense NC_000003.12:g.15644620T>C NC_000003.11:g.15686127T>C NG_008019.2:g.48269T>C NG_008019.3:g.48270T>C - Protein change
- I235T
- Other names
- -
- Canonical SPDI
- NC_000003.12:15644619:T:C
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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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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 | ||
|---|---|---|---|---|---|---|
| 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 |
667 | 753 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 11, 2024 | RCV000021962.11 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Mar 28, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800684.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Likely pathogenic
(Mar 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211490.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Likely pathogenic
(Mar 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922836.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: BTD c.704T>C (p.Ile235Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of the encoded protein sequence. Three … (more)
Variant summary: BTD c.704T>C (p.Ile235Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251440 control chromosomes (gnomAD). c.704T>C has been reported in the literature in at least three compound heterozygous individuals affected with Biotinidase Deficiency (Ohlsson_2010, Jay_2015), who carried a pathogenic variant in trans. In one of the reported patients the biotinidase activity in plasma was immeasurable, suggesting this variant results in profound Biotinidase deficiency (Ohlsson_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic, or as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Likely pathogenic
(Aug 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002266868.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 255 of the BTD protein (p.Ile255Thr). This variant is present in population databases (rs397514384, gnomAD 0.002%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 20224900, 25144890; Invitae). 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: 25040). 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. (less)
|
Comment:
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 255 of the BTD protein (p.Ile255Thr). This variant is present in population databases (rs397514384, gnomAD 0.002%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 20224900, 25144890; Invitae). 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: 25040). 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.
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. |
Comment:
Variant summary: BTD c.704T>C (p.Ile235Thr) results in a non-conservative amino acid change located in the Carbon-nitrogen hydrolase domain (IPR003010) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251440 control chromosomes (gnomAD). c.704T>C has been reported in the literature in at least three compound heterozygous individuals affected with Biotinidase Deficiency (Ohlsson_2010, Jay_2015), who carried a pathogenic variant in trans. In one of the reported patients the biotinidase activity in plasma was immeasurable, suggesting this variant results in profound Biotinidase deficiency (Ohlsson_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic, or as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 255 of the BTD protein (p.Ile255Thr). This variant is present in population databases (rs397514384, gnomAD 0.002%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 20224900, 25144890; Invitae). 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: 25040). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins. | Mao F | Nucleic acids research | 2016 | PMID: 26635394 |
| 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 |
| Analysis of mutations causing biotinidase deficiency. | Pindolia K | Human mutation | 2010 | PMID: 20556795 |
| Profound biotinidase deficiency: a rare disease among native Swedes. | Ohlsson A | Journal of inherited metabolic disease | 2010 | PMID: 20224900 |
Text-mined citations for rs397514384 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.