ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.40G>A (p.Gly14Ser)
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(3); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370658.1(BTD):c.40G>A (p.Gly14Ser)
Variation ID: 1899 Accession: VCV000001899.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15635479 (GRCh38) [ NCBI UCSC ] 3: 15676986 (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 Feb 14, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370658.1:c.40G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Gly14Ser missense NM_000060.4:c.100G>A NP_000051.1:p.Gly34Ser missense NM_001281723.4:c.40G>A NP_001268652.2:p.Gly14Ser missense NM_001281724.3:c.40G>A NP_001268653.2:p.Gly14Ser missense NM_001281725.3:c.40G>A NP_001268654.1:p.Gly14Ser missense NM_001281726.3:c.40G>A NP_001268655.2:p.Gly14Ser missense NM_001323582.2:c.40G>A NP_001310511.1:p.Gly14Ser missense NM_001370752.1:c.40G>A NP_001357681.1:p.Gly14Ser missense NM_001370753.1:c.40G>A NP_001357682.1:p.Gly14Ser missense NM_001407364.1:c.40G>A NP_001394293.1:p.Gly14Ser missense NM_001407365.1:c.40G>A NP_001394294.1:p.Gly14Ser missense NM_001407366.1:c.40G>A NP_001394295.1:p.Gly14Ser missense NM_001407367.1:c.40G>A NP_001394296.1:p.Gly14Ser missense NM_001407368.1:c.40G>A NP_001394297.1:p.Gly14Ser missense NM_001407369.1:c.40G>A NP_001394298.1:p.Gly14Ser missense NM_001407370.1:c.40G>A NP_001394299.1:p.Gly14Ser missense NM_001407371.1:c.40G>A NP_001394300.1:p.Gly14Ser missense NM_001407372.1:c.40G>A NP_001394301.1:p.Gly14Ser missense NM_001407373.1:c.40G>A NP_001394302.1:p.Gly14Ser missense NM_001407374.1:c.40G>A NP_001394303.1:p.Gly14Ser missense NM_001407375.1:c.40G>A NP_001394304.1:p.Gly14Ser missense NM_001407376.1:c.40G>A NP_001394305.1:p.Gly14Ser missense NM_001407377.1:c.40G>A NP_001394306.1:p.Gly14Ser missense NM_001407378.1:c.40G>A NP_001394307.1:p.Gly14Ser missense NM_001407379.1:c.40G>A NP_001394308.1:p.Gly14Ser missense NM_001407380.1:c.40G>A NP_001394309.1:p.Gly14Ser missense NM_001407381.1:c.40G>A NP_001394310.1:p.Gly14Ser missense NM_001407382.1:c.40G>A NP_001394311.1:p.Gly14Ser missense NM_001407383.1:c.40G>A NP_001394312.1:p.Gly14Ser missense NM_001407384.1:c.40G>A NP_001394313.1:p.Gly14Ser missense NM_001407386.1:c.40G>A NP_001394315.1:p.Gly14Ser missense NM_001407388.1:c.40G>A NP_001394317.1:p.Gly14Ser missense NM_001407390.1:c.40G>A NP_001394319.1:p.Gly14Ser missense NM_001407392.1:c.40G>A NP_001394321.1:p.Gly14Ser missense NM_001407394.1:c.40G>A NP_001394323.1:p.Gly14Ser missense NM_001407395.1:c.40G>A NP_001394324.1:p.Gly14Ser missense NM_001407396.1:c.40G>A NP_001394325.1:p.Gly14Ser missense NM_001407397.1:c.40G>A NP_001394326.1:p.Gly14Ser missense NM_001407398.1:c.40G>A NP_001394327.1:p.Gly14Ser missense NM_001407399.1:c.40G>A NP_001394328.1:p.Gly14Ser missense NM_001407400.1:c.40G>A NP_001394329.1:p.Gly14Ser missense NM_001407401.1:c.40G>A NP_001394330.1:p.Gly14Ser missense NC_000003.12:g.15635479G>A NC_000003.11:g.15676986G>A NG_008019.2:g.39128G>A - Protein change
- G14S
- Other names
- G34S
- Canonical SPDI
- NC_000003.12:15635478:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 |
643 | 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 (8) |
criteria provided, conflicting classifications
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Oct 22, 2023 | RCV000001976.19 |
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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Likely pathogenic
(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: SCV001136335.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine
Accession: SCV004047571.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.40G>A (p.Gly14Ser) in BTD gene has been observed to be homozygous or in combination with another BTD variant in several individuals affected … (more)
The missense variant c.40G>A (p.Gly14Ser) in BTD gene has been observed to be homozygous or in combination with another BTD variant in several individuals affected with biotinidase deficiency (Borsatto T et al., 2017). Experimental studies have shown that this missense variant disrupts mRNA splicing (Pomponio et al., 1997). This variant has allele frequency 0.002% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic/ Uncertain Significance. The amino acid Gly at position 14 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly14Ser in BTD is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Seizure (present) , Decreased circulating biotinidase concentration (present) , Nystagmus (present) , Uncontrolled eye movements (present) , Spasticity (present) , … (more)
Global developmental delay (present) , Seizure (present) , Decreased circulating biotinidase concentration (present) , Nystagmus (present) , Uncontrolled eye movements (present) , Spasticity (present) , Myoclonus (present) , Hyperintensity of cerebral white matter on MRI (present) (less)
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Pathogenic
(Aug 02, 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: SCV000934145.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in the activation of a cryptic splice … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 2 (PMID: 9158148). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1899). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9158148, 21752405, 25174816, 31035122). 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 (rs119103232, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 34 of the BTD protein (p.Gly34Ser). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 19 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. (less)
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Uncertain significance
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845357.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Biotinidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001781529.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Sex: male
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Pathogenic
(Oct 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: SCV004211400.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 01, 1997)
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no assertion criteria provided
Method: literature only
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BIOTINIDASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022134.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2020 |
Comment on evidence:
In 2 unrelated individuals with profound biotinidase deficiency (253260), Pomponio et al. (1997) identified a 100G-A transition in the BTD gene, located 57 bases downstream … (more)
In 2 unrelated individuals with profound biotinidase deficiency (253260), Pomponio et al. (1997) identified a 100G-A transition in the BTD gene, located 57 bases downstream of the authentic splice acceptor site in exon B, resulting in a gly34-to-ser (G34S) substitution. The transition also generated a 3-prime splice acceptor site. The sequence of the PCR-amplified cDNA from the homozygous child revealed that all the product was shorter than that of normal individuals and was the result of aberrant splicing. The aberrantly spliced transcript lacks 57 nucleotides, including a second in-frame ATG, that encode most of the putative signal peptide and results in an in-frame deletion of 19 amino acids. The mutation resulted in failure to secrete the aberrant protein into the blood. This was the first reported example in which a point mutation creates a cryptic 3-prime splice acceptor site motif that is used preferentially over the upstream authentic splice site. Pomponio et al. (1997) stated that preferential usage of the downstream splice site was not consistent with the 5-prime-to-3-prime scanning model of RNA splicing, but was consistent with the exon definition model. (less)
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Pathogenic
(Sep 16, 2020)
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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: SCV001460175.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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 deficiency: A treatable cause of opticospinal syndrome in young adults(✰). | Van Iseghem V | Multiple sclerosis and related disorders | 2019 | PMID: 31035122 |
Biotinidase deficiency: clinical and genetic studies of 38 Brazilian patients. | Borsatto T | BMC medical genetics | 2014 | PMID: 25174816 |
[Clinical and genetic findings in patients with biotinidase deficiency detected through newborn screening or selective screening for hearing loss or inherited metabolic disease]. | Couce ML | Medicina clinica | 2011 | PMID: 21752405 |
Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3' splice acceptor site within an exon of the human biotinidase gene. | Pomponio RJ | Human molecular genetics | 1997 | PMID: 9158148 |
Text-mined citations for rs119103232 ...
HelpRecord last updated Feb 14, 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.