ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.908A>G (p.His303Arg)
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(3); Uncertain significance(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370658.1(BTD):c.908A>G (p.His303Arg)
Variation ID: 38278 Accession: VCV000038278.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644824 (GRCh38) [ NCBI UCSC ] 3: 15686331 (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 Mar 8, 2017 Sep 16, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370658.1:c.908A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.His303Arg missense NM_000060.4:c.968A>G NP_000051.1:p.His323Arg missense NM_001281723.4:c.908A>G NP_001268652.2:p.His303Arg missense NM_001281724.3:c.908A>G NP_001268653.2:p.His303Arg missense NM_001281725.3:c.908A>G NP_001268654.1:p.His303Arg missense NM_001281726.2:c.*2686A>G NM_001323582.2:c.908A>G NP_001310511.1:p.His303Arg missense NM_001370752.1:c.908A>G NP_001357681.1:p.His303Arg missense NM_001370753.1:c.399+2767A>G intron variant NM_001407364.1:c.908A>G NP_001394293.1:p.His303Arg missense NM_001407365.1:c.908A>G NP_001394294.1:p.His303Arg missense NM_001407366.1:c.908A>G NP_001394295.1:p.His303Arg missense NM_001407367.1:c.908A>G NP_001394296.1:p.His303Arg missense NM_001407368.1:c.908A>G NP_001394297.1:p.His303Arg missense NM_001407369.1:c.908A>G NP_001394298.1:p.His303Arg missense NM_001407370.1:c.908A>G NP_001394299.1:p.His303Arg missense NM_001407371.1:c.908A>G NP_001394300.1:p.His303Arg missense NM_001407372.1:c.908A>G NP_001394301.1:p.His303Arg missense NM_001407373.1:c.908A>G NP_001394302.1:p.His303Arg missense NM_001407374.1:c.908A>G NP_001394303.1:p.His303Arg missense NM_001407375.1:c.908A>G NP_001394304.1:p.His303Arg missense NM_001407376.1:c.908A>G NP_001394305.1:p.His303Arg missense NM_001407377.1:c.908A>G NP_001394306.1:p.His303Arg missense NM_001407378.1:c.908A>G NP_001394307.1:p.His303Arg missense NM_001407379.1:c.908A>G NP_001394308.1:p.His303Arg missense NM_001407380.1:c.399+2767A>G intron variant NM_001407398.1:c.399+2767A>G intron variant NM_001407399.1:c.399+2767A>G intron variant NM_001407400.1:c.399+2767A>G intron variant NM_001407401.1:c.399+2767A>G intron variant NC_000003.12:g.15644824A>G NC_000003.11:g.15686331A>G NG_008019.2:g.48473A>G NG_008019.3:g.48474A>G P43251:p.His323Arg - Protein change
- H303R
- Other names
- H323R
- Canonical SPDI
- NC_000003.12:15644823:A:G
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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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0.00479 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00205
Exome Aggregation Consortium (ExAC) 0.00232
1000 Genomes Project 30x 0.00437
1000 Genomes Project 0.00479
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
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 |
665 | 750 |
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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 5, 2024 | RCV000021978.23 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2021 | RCV000622271.13 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 9, 2024 | RCV000723564.31 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 31, 2024 | RCV002298452.10 |
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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Uncertain significance
(Nov 15, 2022)
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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: SCV001134045.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
The variant has been described in two heterozygous cases with a severe genotype (PMID: 33217065 (2021)). Analysis of this variant using bioinformatics tools for the … (more)
The variant has been described in two heterozygous cases with a severe genotype (PMID: 33217065 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Taking into account the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jul 31, 2024)
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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: SCV002598712.3
First in ClinVar: Nov 05, 2022 Last updated: Sep 16, 2024 |
Comment:
Variant summary: BTD c.908A>G (p.His303Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: BTD c.908A>G (p.His303Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251360 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in BTD causing Biotinidase Deficiency phenotype (0.0046). c.908A>G has been reported in the literature in individuals affected with Biotinidase Deficiency (e.g. Swango_1998, Al-Jasmi_2016, Mardhiah_2020, Karaoglan_2020, Forny_2022, Sharma_2024, Yilmaz_2024). These reports do not provide unequivocal conclusions about association of the variant with Biotinidase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26589311, 9654207, 33217065, 32300527, 35195902, 38299772, 38141137). ClinVar contains an entry for this variant (Variation ID: 38278). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001136346.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(May 31, 2022)
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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: SCV001522810.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023 |
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Uncertain significance
(Jan 05, 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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Revvity Omics, Revvity
Accession: SCV004234890.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Sep 21, 2021)
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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: SCV000742653.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.968A>G (p.H323R) alteration is located in coding exon 4 of the BTD gene. This alteration results from an A to G substitution at nucleotide … (more)
The c.968A>G (p.H323R) alteration is located in coding exon 4 of the BTD gene. This alteration results from an A to G substitution at nucleotide position 968, causing the histidine (H) at amino acid position 323 to be replaced by an arginine (R). The BTD c.968A>G alteration has been reported previously in the compound heterozygous state in multiple individuals with enzyme levels consistent with partial biotinidase deficiency (Swango, 1998; Li, 2014, Gannavarapu, 2015; Wiltink, 2016; Mardhiah, 2020). The c.968A>G (p.H323R) alteration is considered a hypomorphic allele and only causes disease when in trans with a more severe allele (Lek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Likely pathogenic
(Dec 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821167.12
First in ClinVar: Jan 21, 2023 Last updated: Aug 04, 2024 |
Comment:
BTD: PM2, PM3, PP4:Moderate
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 09, 2024)
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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: SCV000516150.9
First in ClinVar: Mar 08, 2017 Last updated: Sep 16, 2024 |
Comment:
Observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (gnomAD) and healthy adult individuals tested at GeneDx; In silico analysis supports … (more)
Observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (gnomAD) and healthy adult individuals tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.968A>G; p.(H323R); This variant is associated with the following publications: (PMID: 31191208, 24066991, 27535533, 28498829, 27657684, 27329734, 27014582, 26810761, 22698809, 17382128, 9654207, 26361991, 11668630, 32300527, 24797656, 35195902, 36684547) (less)
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Uncertain significance
(Dec 10, 2012)
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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: SCV000109921.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Oct 17, 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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Invitae
Accession: SCV000630341.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BTD protein (p.His323Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 323 of the BTD protein (p.His323Arg). This variant is present in population databases (rs397507176, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with partial BTD deficiency who showed 10-30% of normal BTD enzymatic activity (PMID: 9654207, 26361991). ClinVar contains an entry for this variant (Variation ID: 38278). 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. Experimental studies have shown that this missense change affects BTD function (PMID: 9654207, 24797656). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 25, 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: SCV001454451.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 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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Biotinidase biochemical and molecular analyses: Experience at a large reference laboratory. | Sharma R | Pediatrics international : official journal of the Japan Pediatric Society | 2024 | PMID: 38299772 |
Evaluation of clinical, laboratory, and molecular genetic features of patients with biotinidase deficiency. | Yılmaz B | European journal of pediatrics | 2024 | PMID: 38141137 |
Recovery of enzyme activity in biotinidase deficient individuals during early childhood. | Forny P | Journal of inherited metabolic disease | 2022 | PMID: 35195902 |
Immunophenotypic analysis of lymphocyte subsets in newborns with biotinidase deficiency. | Karaoglan M | Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology | 2021 | PMID: 33217065 |
Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population. | Mardhiah M | Molecular genetics and metabolism reports | 2019 | PMID: 32300527 |
Analysis of protein-coding genetic variation in 60,706 humans. | Lek M | Nature | 2016 | PMID: 27535533 |
Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. | Wiltink RC | European journal of human genetics : EJHG | 2016 | PMID: 27329734 |
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 |
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 |
Biotinidase deficiency: an atypical presentation. | Jagadeesh S | The National medical journal of India | 2013 | PMID: 24066991 |
Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. | Swango KL | Human genetics | 1998 | PMID: 9654207 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BTD | - | - | - | - |
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Text-mined citations for rs397507176 ...
HelpRecord last updated Sep 17, 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.