The BTD c.485C>T; p.Ala162Val variant (rs397514364) is reported in the literature in multiple individuals affected with partial to profound biotinidase deficiency usually found with a second pathogenic variant (Norrgard 1999, Wolf 2017). This variant is reported in ClinVar (Variation ID: 25014) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. Wolf B et al. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. PMID: 27657684.
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.425C>T (p.Ala142Val)
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.
Pathogenic
4
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.425C>T (p.Ala142Val)
Variation ID: 25014 Accession: VCV000025014.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644341 (GRCh38) [ NCBI UCSC ] 3: 15685848 (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 Nov 22, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.425C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Ala142Val missense NM_000060.4:c.485C>T NP_000051.1:p.Ala162Val missense NM_001281723.4:c.425C>T NP_001268652.2:p.Ala142Val missense NM_001281724.3:c.425C>T NP_001268653.2:p.Ala142Val missense NM_001281725.3:c.425C>T NP_001268654.1:p.Ala142Val missense NM_001323582.2:c.425C>T NP_001310511.1:p.Ala142Val missense NM_001370752.1:c.425C>T NP_001357681.1:p.Ala142Val missense NM_001370753.1:c.399+2284C>T intron variant NM_001407364.1:c.425C>T NP_001394293.1:p.Ala142Val missense NM_001407365.1:c.425C>T NP_001394294.1:p.Ala142Val missense NM_001407366.1:c.425C>T NP_001394295.1:p.Ala142Val missense NM_001407367.1:c.425C>T NP_001394296.1:p.Ala142Val missense NM_001407368.1:c.425C>T NP_001394297.1:p.Ala142Val missense NM_001407369.1:c.425C>T NP_001394298.1:p.Ala142Val missense NM_001407370.1:c.425C>T NP_001394299.1:p.Ala142Val missense NM_001407371.1:c.425C>T NP_001394300.1:p.Ala142Val missense NM_001407372.1:c.425C>T NP_001394301.1:p.Ala142Val missense NM_001407373.1:c.425C>T NP_001394302.1:p.Ala142Val missense NM_001407374.1:c.425C>T NP_001394303.1:p.Ala142Val missense NM_001407375.1:c.425C>T NP_001394304.1:p.Ala142Val missense NM_001407376.1:c.425C>T NP_001394305.1:p.Ala142Val missense NM_001407377.1:c.425C>T NP_001394306.1:p.Ala142Val missense NM_001407378.1:c.425C>T NP_001394307.1:p.Ala142Val missense NM_001407379.1:c.425C>T NP_001394308.1:p.Ala142Val missense NC_000003.12:g.15644341C>T NC_000003.11:g.15685848C>T NG_008019.2:g.47990C>T NG_008019.3:g.47991C>T - Protein change
- A142V
- Other names
- -
- Canonical SPDI
- NC_000003.12:15644340: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.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
669 | 755 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 22, 2023 | RCV000021934.19 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049838.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The BTD c.485C>T; p.Ala162Val variant (rs397514364) is reported in the literature in multiple individuals affected with partial to profound biotinidase deficiency usually found with a … (more)
The BTD c.485C>T; p.Ala162Val variant (rs397514364) is reported in the literature in multiple individuals affected with partial to profound biotinidase deficiency usually found with a second pathogenic variant (Norrgard 1999, Wolf 2017). This variant is reported in ClinVar (Variation ID: 25014) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. Wolf B et al. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. PMID: 27657684. (less)
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Pathogenic
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211478.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002313747.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the BTD protein (p.Ala162Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the BTD protein (p.Ala162Val). This variant is present in population databases (rs397514364, gnomAD 0.0009%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 25144890, 27657684). ClinVar contains an entry for this variant (Variation ID: 25014). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 26, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800682.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the BTD protein (p.Ala162Val). This variant is present in population databases (rs397514364, gnomAD 0.0009%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 25144890, 27657684). ClinVar contains an entry for this variant (Variation ID: 25014). 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. For these reasons, this variant has been classified as Pathogenic.
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:
The BTD c.485C>T; p.Ala162Val variant (rs397514364) is reported in the literature in multiple individuals affected with partial to profound biotinidase deficiency usually found with a second pathogenic variant (Norrgard 1999, Wolf 2017). This variant is reported in ClinVar (Variation ID: 25014) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Norrgard KJ et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res. 1999 Jul;46(1):20-7. PMID: 10400129. Wolf B et al. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402. PMID: 27657684.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the BTD protein (p.Ala162Val). This variant is present in population databases (rs397514364, gnomAD 0.0009%). This missense change has been observed in individual(s) with BTD-related conditions (PMID: 25144890, 27657684). ClinVar contains an entry for this variant (Variation ID: 25014). 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. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
| Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. | Norrgard KJ | Pediatric research | 1999 | PMID: 10400129 |
Text-mined citations for rs397514364 ...
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.