For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099842, 22698809, 27207447, 27657684). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). 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. ClinVar contains an entry for this variant (Variation ID: 25099). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26810761, 29359854; Invitae). 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 (rs397514429, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the BTD protein (p.Arg538His).
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.1553G>A (p.Arg518His)
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.
(5)
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001370658.1(BTD):c.1553G>A (p.Arg518His)
Variation ID: 25099 Accession: VCV000025099.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.1 3: 15645469 (GRCh38) [ NCBI UCSC ] 3: 15686976 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 23, 2024 Dec 12, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.1553G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Arg518His missense NM_000060.4:c.1613G>A NP_000051.1:p.Arg538His missense NM_001281723.4:c.1553G>A NP_001268652.2:p.Arg518His missense NM_001281724.3:c.1553G>A NP_001268653.2:p.Arg518His missense NM_001281725.3:c.1553G>A NP_001268654.1:p.Arg518His missense NM_001323582.2:c.1553G>A NP_001310511.1:p.Arg518His missense NM_001370752.1:c.1015+538G>A intron variant NM_001370753.1:c.399+3412G>A intron variant NM_001407364.1:c.1553G>A NP_001394293.1:p.Arg518His missense NM_001407365.1:c.1553G>A NP_001394294.1:p.Arg518His missense NM_001407366.1:c.1553G>A NP_001394295.1:p.Arg518His missense NM_001407367.1:c.1553G>A NP_001394296.1:p.Arg518His missense NM_001407368.1:c.1553G>A NP_001394297.1:p.Arg518His missense NM_001407369.1:c.1553G>A NP_001394298.1:p.Arg518His missense NM_001407370.1:c.1553G>A NP_001394299.1:p.Arg518His missense NM_001407371.1:c.1553G>A NP_001394300.1:p.Arg518His missense NM_001407372.1:c.1553G>A NP_001394301.1:p.Arg518His missense NM_001407373.1:c.1553G>A NP_001394302.1:p.Arg518His missense NM_001407374.1:c.1553G>A NP_001394303.1:p.Arg518His missense NM_001407375.1:c.1553G>A NP_001394304.1:p.Arg518His missense NM_001407376.1:c.1553G>A NP_001394305.1:p.Arg518His missense NM_001407377.1:c.1553G>A NP_001394306.1:p.Arg518His missense NM_001407378.1:c.1553G>A NP_001394307.1:p.Arg518His missense NC_000003.12:g.15645469G>A NC_000003.11:g.15686976G>A NG_008019.2:g.49118G>A NG_008019.3:g.49119G>A - Protein change
- R518H
- Other names
- -
- Canonical SPDI
- NC_000003.12:15645468:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 |
670 | 756 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000022024.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2023 | RCV004589521.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211480.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Likely pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022093.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001588464.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099842, 22698809, 27207447, 27657684). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). 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. ClinVar contains an entry for this variant (Variation ID: 25099). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26810761, 29359854; Invitae). 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 (rs397514429, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the BTD protein (p.Arg538His). (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005073891.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
The observed missense c.1553G>A (p.Arg518His) variant in gene has been reported in compound heterozygous state in individuals affected with Biotinidase deficiency (Procter M et al. … (more)
The observed missense c.1553G>A (p.Arg518His) variant in gene has been reported in compound heterozygous state in individuals affected with Biotinidase deficiency (Procter M et al. 2016). Experimental studies have shown that this missense change affects BTD function (Liu Z et al. 2018). The variant p.Arg518His has allele frequency 0.0004% in gnomAD. This variant has been submitted to the ClinVar database as likely Pathogenic / Pathogenic. The amino acid change p.Arg518His in BTD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 518 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005078669.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R538H); This variant is associated with the following publications: (PMID: 19757147, 29359854, 26810761, 22698809, 9099842, 27657684, 27207447, 37564434) (less)
|
Comment:
Comment:
The observed missense c.1553G>A (p.Arg518His) variant in gene has been reported in compound heterozygous state in individuals affected with Biotinidase deficiency (Procter M et al. 2016). Experimental studies have shown that this missense change affects BTD function (Liu Z et al. 2018). The variant p.Arg518His has allele frequency 0.0004% in gnomAD. This variant has been submitted to the ClinVar database as likely Pathogenic / Pathogenic. The amino acid change p.Arg518His in BTD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 518 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R538H); This variant is associated with the following publications: (PMID: 19757147, 29359854, 26810761, 22698809, 9099842, 27657684, 27207447, 37564434)
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:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg538 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9099842, 22698809, 27207447, 27657684). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BTD function (PMID: 29359854). 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. ClinVar contains an entry for this variant (Variation ID: 25099). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26810761, 29359854; Invitae). 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 (rs397514429, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the BTD protein (p.Arg538His).
Comment:
The observed missense c.1553G>A (p.Arg518His) variant in gene has been reported in compound heterozygous state in individuals affected with Biotinidase deficiency (Procter M et al. 2016). Experimental studies have shown that this missense change affects BTD function (Liu Z et al. 2018). The variant p.Arg518His has allele frequency 0.0004% in gnomAD. This variant has been submitted to the ClinVar database as likely Pathogenic / Pathogenic. The amino acid change p.Arg518His in BTD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 518 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R538H); This variant is associated with the following publications: (PMID: 19757147, 29359854, 26810761, 22698809, 9099842, 27657684, 27207447, 37564434)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical features, BTD gene mutations, and their functional studies of eight symptomatic patients with biotinidase deficiency from Southern China. | Liu Z | American journal of medical genetics. Part A | 2018 | PMID: 29359854 |
| 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 |
| Biotinidase deficiency mimicking neuromyelitis optica beginning at the age of 4: A treatable disease. | Girard B | Multiple sclerosis (Houndmills, Basingstoke, England) | 2017 | PMID: 27207447 |
| Forty-eight novel mutations causing biotinidase deficiency. | Procter M | Molecular genetics and metabolism | 2016 | PMID: 26810761 |
| Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. | Cowan TM | Molecular genetics and metabolism | 2012 | PMID: 22698809 |
| High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota. | Sarafoglou K | Journal of inherited metabolic disease | 2009 | PMID: 19757147 |
| Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. | Pomponio RJ | Human genetics | 1997 | PMID: 9099842 |
Text-mined citations for rs397514429 ...
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 13, 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.