ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.565C>T (p.Arg189Cys)
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.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370658.1(BTD):c.565C>T (p.Arg189Cys)
Variation ID: 458809 Accession: VCV000458809.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644481 (GRCh38) [ NCBI UCSC ] 3: 15685988 (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 Dec 26, 2017 Feb 28, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370658.1:c.565C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Arg189Cys missense NM_000060.4:c.625C>T NP_000051.1:p.Arg209Cys missense NM_001281723.4:c.565C>T NP_001268652.2:p.Arg189Cys missense NM_001281724.3:c.565C>T NP_001268653.2:p.Arg189Cys missense NM_001281725.3:c.565C>T NP_001268654.1:p.Arg189Cys missense NM_001323582.2:c.565C>T NP_001310511.1:p.Arg189Cys missense NM_001370752.1:c.565C>T NP_001357681.1:p.Arg189Cys missense NM_001370753.1:c.399+2424C>T intron variant NM_001407364.1:c.565C>T NP_001394293.1:p.Arg189Cys missense NM_001407365.1:c.565C>T NP_001394294.1:p.Arg189Cys missense NM_001407366.1:c.565C>T NP_001394295.1:p.Arg189Cys missense NM_001407367.1:c.565C>T NP_001394296.1:p.Arg189Cys missense NM_001407368.1:c.565C>T NP_001394297.1:p.Arg189Cys missense NM_001407369.1:c.565C>T NP_001394298.1:p.Arg189Cys missense NM_001407370.1:c.565C>T NP_001394299.1:p.Arg189Cys missense NM_001407371.1:c.565C>T NP_001394300.1:p.Arg189Cys missense NM_001407372.1:c.565C>T NP_001394301.1:p.Arg189Cys missense NM_001407373.1:c.565C>T NP_001394302.1:p.Arg189Cys missense NM_001407374.1:c.565C>T NP_001394303.1:p.Arg189Cys missense NM_001407375.1:c.565C>T NP_001394304.1:p.Arg189Cys missense NM_001407376.1:c.565C>T NP_001394305.1:p.Arg189Cys missense NM_001407377.1:c.565C>T NP_001394306.1:p.Arg189Cys missense NM_001407378.1:c.565C>T NP_001394307.1:p.Arg189Cys missense NM_001407379.1:c.565C>T NP_001394308.1:p.Arg189Cys missense NC_000003.12:g.15644481C>T NC_000003.11:g.15685988C>T NG_008019.2:g.48130C>T NG_008019.3:g.48131C>T - Protein change
- R189C
- Other names
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- Canonical SPDI
- NC_000003.12:15644480: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.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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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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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 21, 2024 | RCV000537387.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2023 | RCV001591206.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 6, 2021 | RCV001778993.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 19, 2022 | RCV002527692.1 |
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
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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
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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
(Oct 05, 2017)
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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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Counsyl
Accession: SCV000788646.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001652750.1
First in ClinVar: May 28, 2021 Last updated: May 28, 2021 |
Sex: mixed
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Uncertain significance
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015196.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: BTD c.565C>T (p.Arg189Cys), also known as c.625C>T (p.R209C), results in a non-conservative amino acid change in the encoded protein sequence. Five of five … (more)
Variant summary: BTD c.565C>T (p.Arg189Cys), also known as c.625C>T (p.R209C), 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 5.6e-05 in 251480 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.565C>T has been reported in the literature in individuals affected with Biotinidase Deficiency as well as in two asymptomatic infants (Procter_2016, Tanyalcin_2016, Seker Yilmaz_2018, Ercan_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Sep 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003697307.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.625C>T (p.R209C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution … (more)
The c.625C>T (p.R209C) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution at nucleotide position 625, causing the arginine (R) at amino acid position 209 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001814815.2
First in ClinVar: Sep 08, 2021 Last updated: Aug 31, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27760515, 29353266, 34426522, 34271776, 33189081, 26810761) (less)
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Likely pathogenic
(Oct 23, 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: SCV004211398.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 21, 2024)
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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: SCV000630339.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 209 of the BTD protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 209 of the BTD protein (p.Arg209Cys). This variant is present in population databases (rs369102875, gnomAD 0.008%). This missense change has been observed in individuals with biotinidase deficiency (PMID: 26810761, 33189081; Invitae). ClinVar contains an entry for this variant (Variation ID: 458809). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg209 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24797656, 25754625, 26361991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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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Evaluation of the efficiency of serum biotinidase activity as a newborn screening test in Turkey. | Ercan M | Journal of pediatric endocrinology & metabolism : JPEM | 2020 | PMID: 33189081 |
Twenty-seven mutations with three novel pathologenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey. | Seker Yilmaz B | Journal of pediatric endocrinology & metabolism : JPEM | 2018 | PMID: 29353266 |
Convert your favorite protein modeling program into a mutation predictor: "MODICT". | Tanyalcin I | BMC bioinformatics | 2016 | PMID: 27760515 |
Forty-eight novel mutations causing biotinidase deficiency. | Procter M | Molecular genetics and metabolism | 2016 | PMID: 26810761 |
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 |
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 |
Abstracts of ICIEM 2013, the 12th International Congress of Inborn Errors of Metabolism. Barcelona, Spain. September 3-6, 2013. | - | Journal of inherited metabolic disease | 2013 | PMID: 23971085 |
Text-mined citations for rs369102875 ...
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.