NM_000060.2(BTD):c.755A>G(D252G) is classified as pathogenic in the context of biotinidase deficiency and is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 10400129, 25174816, 15060693, 22698809 and 26361991. Classification of NM_000060.2(BTD):c.755A>G(D252G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
ClinVar Genomic variation as it relates to human health
NM_001370658.1(BTD):c.695A>G (p.Asp232Gly)
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.
(8)
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
8
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.695A>G (p.Asp232Gly)
Variation ID: 1901 Accession: VCV000001901.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.1 3: 15644611 (GRCh38) [ NCBI UCSC ] 3: 15686118 (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 Aug 16, 2015 Jun 17, 2024 Mar 27, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001370658.1:c.695A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357587.1:p.Asp232Gly missense NM_000060.4:c.755A>G NP_000051.1:p.Asp252Gly missense NM_001281723.4:c.695A>G NP_001268652.2:p.Asp232Gly missense NM_001281724.3:c.695A>G NP_001268653.2:p.Asp232Gly missense NM_001281725.3:c.695A>G NP_001268654.1:p.Asp232Gly missense NM_001323582.2:c.695A>G NP_001310511.1:p.Asp232Gly missense NM_001370752.1:c.695A>G NP_001357681.1:p.Asp232Gly missense NM_001370753.1:c.399+2554A>G intron variant NM_001407364.1:c.695A>G NP_001394293.1:p.Asp232Gly missense NM_001407365.1:c.695A>G NP_001394294.1:p.Asp232Gly missense NM_001407366.1:c.695A>G NP_001394295.1:p.Asp232Gly missense NM_001407367.1:c.695A>G NP_001394296.1:p.Asp232Gly missense NM_001407368.1:c.695A>G NP_001394297.1:p.Asp232Gly missense NM_001407369.1:c.695A>G NP_001394298.1:p.Asp232Gly missense NM_001407370.1:c.695A>G NP_001394299.1:p.Asp232Gly missense NM_001407371.1:c.695A>G NP_001394300.1:p.Asp232Gly missense NM_001407372.1:c.695A>G NP_001394301.1:p.Asp232Gly missense NM_001407373.1:c.695A>G NP_001394302.1:p.Asp232Gly missense NM_001407374.1:c.695A>G NP_001394303.1:p.Asp232Gly missense NM_001407375.1:c.695A>G NP_001394304.1:p.Asp232Gly missense NM_001407376.1:c.695A>G NP_001394305.1:p.Asp232Gly missense NM_001407377.1:c.695A>G NP_001394306.1:p.Asp232Gly missense NM_001407378.1:c.695A>G NP_001394307.1:p.Asp232Gly missense NM_001407379.1:c.695A>G NP_001394308.1:p.Asp232Gly missense NC_000003.12:g.15644611A>G NC_000003.11:g.15686118A>G NG_008019.2:g.48260A>G NG_008019.3:g.48261A>G - Protein change
- D232G
- Other names
-
D252G
- Canonical SPDI
- NC_000003.12:15644610: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
- 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 |
667 | 753 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000001978.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 6, 2022 | RCV000445043.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193864.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000060.2(BTD):c.755A>G(D252G) is classified as pathogenic in the context of biotinidase deficiency and is seen in patients with both partial and profound biotinidase deficiency. Sources cited … (more)
NM_000060.2(BTD):c.755A>G(D252G) is classified as pathogenic in the context of biotinidase deficiency and is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 10400129, 25174816, 15060693, 22698809 and 26361991. Classification of NM_000060.2(BTD):c.755A>G(D252G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Oct 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600947.2
First in ClinVar: Mar 08, 2017 Last updated: Jan 01, 2022 |
|
|
|
Pathogenic
(Sep 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000516019.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
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; This variant is associated with the following publications: (PMID: 27065010, 15060693, 9375914, 22698809, 11668630, 31801038, 27657684, 25174816, 22975760, 26361991, 28498829, 27629047, 26810761, 10400129) (less)
|
|
|
Pathogenic
(Nov 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000833941.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the BTD protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the BTD protein (p.Asp252Gly). This variant is present in population databases (rs28934601, gnomAD 0.009%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809, 26810761, 27629047, 27657684, 28498829). ClinVar contains an entry for this variant (Variation ID: 1901). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040977.2
First in ClinVar: Oct 07, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894299.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Nov 28, 1997)
|
no assertion criteria provided
Method: literature only
|
BIOTINIDASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022136.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2020 |
Comment on evidence:
In an asymptomatic woman with biotinidase deficiency (253260) who was diagnosed after her child was identified by newborn screening, Wolf et al. (1997) identified a … (more)
In an asymptomatic woman with biotinidase deficiency (253260) who was diagnosed after her child was identified by newborn screening, Wolf et al. (1997) identified a homozygous 755A-G transition, resulting in an asp252-to-gly (D252G) substitution. Her parents were heterozygous for the mutation. Her husband was heterozygous for a missense mutation (Q456H; 609019.0007). The enzyme-deficient daughter was a compound heterozygote for the mutations found in the mother and father. The son, who was identified through newborn screening, was presumably also a compound heterozygote for these 2 mutations. (less)
|
|
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Biotinidase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461220.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
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; This variant is associated with the following publications: (PMID: 27065010, 15060693, 9375914, 22698809, 11668630, 31801038, 27657684, 25174816, 22975760, 26361991, 28498829, 27629047, 26810761, 10400129)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the BTD protein (p.Asp252Gly). This variant is present in population databases (rs28934601, gnomAD 0.009%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809, 26810761, 27629047, 27657684, 28498829). ClinVar contains an entry for this variant (Variation ID: 1901). 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%. 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:
NM_000060.2(BTD):c.755A>G(D252G) is classified as pathogenic in the context of biotinidase deficiency and is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 10400129, 25174816, 15060693, 22698809 and 26361991. Classification of NM_000060.2(BTD):c.755A>G(D252G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
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; This variant is associated with the following publications: (PMID: 27065010, 15060693, 9375914, 22698809, 11668630, 31801038, 27657684, 25174816, 22975760, 26361991, 28498829, 27629047, 26810761, 10400129)
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the BTD protein (p.Asp252Gly). This variant is present in population databases (rs28934601, gnomAD 0.009%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809, 26810761, 27629047, 27657684, 28498829). ClinVar contains an entry for this variant (Variation ID: 1901). 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%. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients. | Borsatto T | PloS one | 2017 | PMID: 28498829 |
| 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 |
| Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia. | Alfadhel M | Orphanet journal of rare diseases | 2016 | PMID: 27629047 |
| 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 |
| Biotinidase deficiency: clinical and genetic studies of 38 Brazilian patients. | Borsatto T | BMC medical genetics | 2014 | PMID: 25174816 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. | Cowan TM | Molecular genetics and metabolism | 2012 | PMID: 22698809 |
| Newborn screening for biotinidase deficiency in Brazil: biochemical and molecular characterizations. | Neto EC | Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas | 2004 | PMID: 15060693 |
| Mutations in BTD causing biotinidase deficiency. | Hymes J | Human mutation | 2001 | PMID: 11668630 |
| 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 |
| Profound biotinidase deficiency in two asymptomatic adults. | Wolf B | American journal of medical genetics | 1997 | PMID: 9375914 |
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Text-mined citations for rs28934601 ...
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.